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Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr 2025; 14:101982. [DOI: 10.5409/wjcp.v14.i2.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Shailja Tibrewal
- Department of Pediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Ria Ratna
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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Yin K, Li M, Zhang H, Chang J, Qi Q, Zhou X, Guo J, Wang Y, Mao X, Hao N, Jiang Y. Optical genome mapping to decipher the chromosomal aberrations in families seeking for preconception genetic counseling. Sci Rep 2025; 15:2614. [PMID: 39838026 PMCID: PMC11751393 DOI: 10.1038/s41598-025-86828-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 01/14/2025] [Indexed: 01/23/2025] Open
Abstract
Optical genome mapping (OGM) offers high consistency in simultaneously detecting structural and copy number variants. This study aimed to retrospectively evaluate the efficacy and potential applications of OGM in preconception genetic counseling. Herein, 74 samples from 37 families were included, and their results of OGM were compared to conventional methods, namely karyotyping (KT) and chromosomal microarray analysis (CMA), which identified 27 variants across 16 positive families. Notably, OGM achieved a concordance rate of 94.7% and 100% with KT and CMA, respectively, presenting an overall concordance of 96.3%, as it missed detecting a centromeric translocation. Additionally, OGM detected two cryptic balanced translocations and a small deletion in three families that were missed by conventional methods, improving the diagnostic rate by 5.4%, along with assisting in the diagnoses of six families (16.2%) by identifying complex rearrangements and confirming cryptic translocations. The combination of KT with OGM yielded the highest diagnostic rate in all families. Overall, the findings of this study present the notable potential of OGM for its application, combined with KT per requirement, in clinical settings to improve the efficiency and accuracy of diagnoses and rapid screening of individuals seeking preconception genetic counseling.
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Affiliation(s)
- Kaili Yin
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mengmeng Li
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hanzhe Zhang
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiazhen Chang
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Qingwei Qi
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiya Zhou
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | | | - Yaru Wang
- Ecobono (Beijing) Biotech Co., Ltd, Beijing, China
| | - Xuequn Mao
- Haidian District Maternal and Child Health Care Hospital, Beijing, China
| | - Na Hao
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Yulin Jiang
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Azuma N, Tadokoro K, Yamada M, Nakafuku M, Nishina H. Sonic Hedgehog Determines Early Retinal Development and Adjusts Eyeball Architecture. Int J Mol Sci 2025; 26:496. [PMID: 39859210 PMCID: PMC11764597 DOI: 10.3390/ijms26020496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
The eye primordium of vertebrates initially forms exactly at the side of the head. Later, the eyeball architecture is tuned to see ahead with better visual acuity, but its molecular basis is unknown. The position of both eyes in the face alters in patients with holoprosencephaly due to Sonic hedgehog (Shh) mutations that disturb the development of the ventral midline of the neural tube. However, patient phenotypes vary extensively, and microforms without a brain anomaly relate instead to alternation of gene expression of the Shh signaling center in the facial primordia. We identified novel missense mutations of the Shh gene in two patients with a dislocated fovea, where the photoreceptor cells are condensed. Functional assays showed that Shh upregulates Patched and Gli and downregulates Pax6, and that Shh mutations alter these activities. Gain of function of Shh in a chick embryo retards retinal development and eyeball growth depending on the location of Shh expression, while loss of function of Shh promotes these features. We postulate that a signaling molecule like Shh that emanates from the face controls the extent of differentiation of the neural retina in a position-specific manner and that this may result in the formation of the fovea at the correct location.
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Affiliation(s)
- Noriyuki Azuma
- Department of Ophthalmology and Laboratory for Visual Science, National Centre for Child Health and Development, Tokyo 157-8535, Japan
- Department of Developmental and Regenerative Biology, Medical Research Institute, Institute of Science Tokyo, Tokyo 113-8510, Japan;
| | - Keiko Tadokoro
- Department of Genetics, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; (K.T.); (M.Y.)
| | - Masao Yamada
- Department of Genetics, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; (K.T.); (M.Y.)
| | - Masato Nakafuku
- Department of Neuroscience, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
- Division of Developmental Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH 45229, USA
| | - Hiroshi Nishina
- Department of Developmental and Regenerative Biology, Medical Research Institute, Institute of Science Tokyo, Tokyo 113-8510, Japan;
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du Plessis AJ, Volpe JJ. Prosencephalic Development. VOLPE'S NEUROLOGY OF THE NEWBORN 2025:38-65.e5. [DOI: 10.1016/b978-0-443-10513-5.00002-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Berkhout JH, Glazier JA, Piersma AH, Belmonte JM, Legler J, Spencer RM, Knudsen TB, Heusinkveld HJ. A computational dynamic systems model for in silico prediction of neural tube closure defects. Curr Res Toxicol 2024; 8:100210. [PMID: 40034255 PMCID: PMC11875186 DOI: 10.1016/j.crtox.2024.100210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 03/05/2025] Open
Abstract
Neural tube closure is a critical morphogenetic event during early vertebrate development. This complex process is susceptible to perturbation by genetic errors and chemical disruption, which can induce severe neural tube defects (NTDs) such as spina bifida. We built a computational agent-based model (ABM) of neural tube development based on the known biology of morphogenetic signals and cellular biomechanics underlying neural fold elevation, bending and fusion. The computer model functionalizes cell signals and responses to render a dynamic representation of neural tube closure. Perturbations in the control network can then be introduced synthetically or from biological data to yield quantitative simulation and probabilistic prediction of NTDs by incidence and degree of defect. Translational applications of the model include mechanistic understanding of how singular or combinatorial alterations in gene-environmental interactions and animal-free assessment of developmental toxicity for an important human birth defect (spina bifida) and potentially other neurological problems linked to development of the brain and spinal cord.
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Affiliation(s)
- Job H. Berkhout
- Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands
| | | | - Aldert H. Piersma
- Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands
| | | | - Juliette Legler
- Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands
| | | | - Thomas B. Knudsen
- Biocomplexity Institute, Indiana University, Bloomington, USA
- U.S. EPA/ORD, Research Triangle Park, NC, USA
| | - Harm J. Heusinkveld
- Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
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Yamada M, Mizuno S, Inaba M, Uehara T, Inagaki H, Suzuki H, Miya F, Takenouchi T, Kurahashi H, Kosaki K. Truncating variants of the sterol recognition region of SHH cause hypertelorism phenotype rather than hypotelorism-holoprosencephaly. Am J Med Genet A 2024; 194:e63614. [PMID: 38562108 DOI: 10.1002/ajmg.a.63614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/04/2024] [Accepted: 03/16/2024] [Indexed: 04/04/2024]
Abstract
Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia-mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss-of-function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13-year-old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of SHH: Chr7(GRCh38):g.155802987C > T, NM_000193.4:c.1302G > A, p.(Trp434*). The second patient was a 25-year-old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of SHH: Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism-holoprosencephaly phenotype associated with loss-of-function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism.
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Affiliation(s)
- Mamiko Yamada
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Seiji Mizuno
- Department of Pediatrics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Japan
| | - Mie Inaba
- Department of Pediatrics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Japan
| | - Tomoko Uehara
- Department of Pediatrics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Japan
| | - Hidehito Inagaki
- Division of Molecular Genetics, Center for Medical Science, Fujita Health University, Toyoake, Japan
| | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Fuyuki Miya
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Toshiki Takenouchi
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Hiroki Kurahashi
- Division of Molecular Genetics, Center for Medical Science, Fujita Health University, Toyoake, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
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Li D, Cheng K, Zhu X. Construction and Identification of a Novel Mice Model of Microphthalmia. Transl Vis Sci Technol 2024; 13:11. [PMID: 39007834 PMCID: PMC467107 DOI: 10.1167/tvst.13.7.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 05/30/2024] [Indexed: 07/16/2024] Open
Abstract
Purpose Microphthalmia is a rare developmental eye disease that affects 1 in 7000 births. Currently, there is no cure for this condition. This study aimed to construct a stable mouse model of microphthalmia, thus providing a new tool for the study of the etiology of microphthalmia. Methods The Hedgehog signaling pathway plays a crucial role in eye development. One of the key mechanisms of the Sonic Hedgehog signaling is the strong transcriptional activation ability of GLI3, a major mediator of this pathway. This study used CRISPR/Cas9 system to construct a novel TgGli3Ki/Ki lens-specific over-expression mouse line. To identify the ocular characteristics of this line, quantitative PCR, Western blot, hematoxylin and eosin staining, immunofluorescent staining, and RNA-seq were performed on the ocular tissues of this line and normal mice. Results The TgGli3Ki/Ki lens-specific over-expression mouse model exhibits the ocular phenotype of microphthalmia. In the TgGli3Ki/Ki mouse, Gli3 is over-expressed in the lens, and the size of the eyeball and lens is significantly smaller than the normal one. RNA-seq analysis using the lens and the retina samples from TgGli3Ki/Ki and normal mice indicates that the phototransduction pathway is ectopically activated in the lens. Immunofluorescent staining of the lens samples confirmed this activation. Conclusions The TgGli3Ki/Ki mouse model consistently manifests the stereotypical microphthalmia phenotype across generations, making it an excellent tool for studying this severe eye disease. Translational Relevance This study developed a novel animal model to facilitate clinical research on microphthalmia.
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Affiliation(s)
- Dan Li
- Eye Institute, Eye & ENT Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China
- Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
| | - Kaiwen Cheng
- Eye Institute, Eye & ENT Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China
- Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xiangjia Zhu
- Eye Institute, Eye & ENT Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China
- Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
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Nishio Y, Kato K, Oishi H, Takahashi Y, Saitoh S. MYCN in human development and diseases. Front Oncol 2024; 14:1417607. [PMID: 38884091 PMCID: PMC11176553 DOI: 10.3389/fonc.2024.1417607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
Somatic mutations in MYCN have been identified across various tumors, playing pivotal roles in tumorigenesis, tumor progression, and unfavorable prognoses. Despite its established notoriety as an oncogenic driver, there is a growing interest in exploring the involvement of MYCN in human development. While MYCN variants have traditionally been associated with Feingold syndrome type 1, recent discoveries highlight gain-of-function variants, specifically p.(Thr58Met) and p.(Pro60Leu), as the cause for megalencephaly-polydactyly syndrome. The elucidation of cellular and murine analytical data from both loss-of-function (Feingold syndrome model) and gain-of-function models (megalencephaly-polydactyly syndrome model) is significantly contributing to a comprehensive understanding of the physiological role of MYCN in human development and pathogenesis. This review discusses the MYCN's functional implications for human development by reviewing the clinical characteristics of these distinct syndromes, Feingold syndrome, and megalencephaly-polydactyly syndrome, providing valuable insights into the understanding of pathophysiological backgrounds of other syndromes associated with the MYCN pathway and the overall comprehension of MYCN's role in human development.
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Affiliation(s)
- Yosuke Nishio
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Kohji Kato
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinji Saitoh
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Egilmezer E, Hamilton ST, Foster CSP, Marschall M, Rawlinson WD. Human cytomegalovirus (CMV) dysregulates neurodevelopmental pathways in cerebral organoids. Commun Biol 2024; 7:340. [PMID: 38504123 PMCID: PMC10951402 DOI: 10.1038/s42003-024-05923-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 02/16/2024] [Indexed: 03/21/2024] Open
Abstract
Human cytomegalovirus (CMV) infection is the leading non-genetic aetiology of congenital malformation in developed countries, causing significant fetal neurological injury. This study investigated potential CMV pathogenetic mechanisms of fetal neural malformation using in vitro human cerebral organoids. Cerebral organoids were permissive to CMV replication, and infection dysregulated cellular pluripotency and differentiation pathways. Aberrant expression of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK), sonic hedgehog (SHH), pluripotency, neurodegeneration, axon guidance, hippo signalling and dopaminergic synapse pathways were observed in CMV-infected organoids using immunofluorescence and RNA-sequencing. Infection with CMV resulted in dysregulation of 236 Autism Spectrum Disorder (ASD)-related genes (p = 1.57E-05) and pathways. This notable observation suggests potential links between congenital CMV infection and ASD. Using DisGeNET databases, 103 diseases related to neural malformation or mental disorders were enriched in CMV-infected organoids. Cytomegalovirus infection-related dysregulation of key cerebral cellular pathways potentially provides important, modifiable pathogenetic mechanisms for congenital CMV-induced neural malformation and ASD.
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Affiliation(s)
- Ece Egilmezer
- Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, 2031, Australia
- School of Medical Science, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Stuart T Hamilton
- Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, 2031, Australia
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Charles S P Foster
- Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, 2031, Australia
- School of Medical Science, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Manfred Marschall
- Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, 91054, Germany
| | - William D Rawlinson
- Serology and Virology Division, Microbiology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, 2031, Australia.
- School of Medical Science, University of New South Wales, Sydney, NSW, 2052, Australia.
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
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Wu C, Liu H, Zhan Z, Zhang X, Zhang M, You J, Ma J. Unveiling dysregulated lncRNAs and networks in non-syndromic cleft lip with or without cleft palate pathogenesis. Sci Rep 2024; 14:1047. [PMID: 38200098 PMCID: PMC10781966 DOI: 10.1038/s41598-024-51747-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/09/2024] [Indexed: 01/12/2024] Open
Abstract
Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common congenital facial malformation with a complex, incompletely understood origin. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators of gene expression, potentially shedding light on NSCL/P's etiology. This study aimed to identify critical lncRNAs and construct regulatory networks to unveil NSCL/P's underlying molecular mechanisms. Integrating gene expression profiles from the Gene Expression Omnibus (GEO) database, we pinpointed 30 dysregulated NSCL/P-associated lncRNAs. Subsequent analyses enabled the creation of competing endogenous RNA (ceRNA) networks, lncRNA-RNA binding protein (RBP) interaction networks, and lncRNA cis and trans regulation networks. RT-qPCR was used to examine the regulatory networks of lncRNA in vivo and in vitro. Furthermore, protein levels of lncRNA target genes were validated in human NSCL/P tissue samples and murine palatal shelves. Consequently, two lncRNAs and three mRNAs: FENDRR (log2FC = - 0.671, P = 0.040), TPT1-AS1 (log2FC = 0.854, P = 0.003), EIF3H (log2FC = - 1.081, P = 0.041), RBBP6 (log2FC = 0.914, P = 0.037), and SRSF1 (log2FC = 0.763, P = 0.026) emerged as potential contributors to NSCL/P pathogenesis. Functional enrichment analyses illuminated the biological functions and pathways associated with these lncRNA-related networks in NSCL/P. In summary, this study comprehensively delineates the dysregulated transcriptional landscape, identifies associated lncRNAs, and reveals pivotal sub-networks relevant to NSCL/P development, aiding our understanding of its molecular progression and setting the stage for further exploration of lncRNA and mRNA regulation in NSCL/P.
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Affiliation(s)
- Caihong Wu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
- Stomatological Hospital affiliated Suzhou Vocational Health College, Suzhou, China
| | - Haojie Liu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Zhuorong Zhan
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Xinyu Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Mengnan Zhang
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Jiawen You
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China
| | - Junqing Ma
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
- Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
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Kulkarni PP, Ekhlak M, Dash D. Non-canonical non-genomic morphogen signaling in anucleate platelets: a critical determinant of prothrombotic function in circulation. Cell Commun Signal 2024; 22:13. [PMID: 38172855 PMCID: PMC10763172 DOI: 10.1186/s12964-023-01448-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024] Open
Abstract
Circulating platelets derived from bone marrow megakaryocytes play a central role in thrombosis and hemostasis. Despite being anucleate, platelets express several proteins known to have nuclear niche. These include transcription factors and steroid receptors whose non-genomic functions are being elucidated in platelets. Quite remarkably, components of some of the best-studied morphogen pathways, namely Notch, Sonic Hedgehog (Shh), and Wnt have also been described in recent years in platelets, which regulate platelet function in the context of thrombosis as well as influence their survival. Shh and Notch pathways in stimulated platelets establish feed-forward loops of autocrine/juxtacrine/paracrine non-canonical signaling that helps perpetuate thrombosis. On the other hand, non-canonical Wnt signaling is part of a negative feedback loop for restricting platelet activation and possibly limiting thrombus growth. The present review will provide an overview of these signaling pathways in general. We will then briefly discuss the non-genomic roles of transcription factors and steroid receptors in platelet activation. This will be followed by an elaborate description of morphogen signaling in platelets with a focus on their bearing on platelet activation leading to hemostasis and thrombosis as well as their potential for therapeutic targeting in thrombotic disorders.
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Affiliation(s)
- Paresh P Kulkarni
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India.
| | - Mohammad Ekhlak
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
| | - Debabrata Dash
- Center for Advanced Research on Platelet Signaling and Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India.
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12
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Cai E, Barba MG, Ge X. Hedgehog Signaling in Cortical Development. Cells 2023; 13:21. [PMID: 38201225 PMCID: PMC10778342 DOI: 10.3390/cells13010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex.
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Affiliation(s)
| | | | - Xuecai Ge
- Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, Merced, CA 95340, USA
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13
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Yan S, Fu F, Li R, Yu Q, Li F, Zhou H, Wang Y, Huang R, Ma C, Guo F, Wang D, Yang X, Han J, Lei T, Li D, Liao C. Exome sequencing improves genetic diagnosis of congenital orofacial clefts. Front Genet 2023; 14:1252823. [PMID: 37745857 PMCID: PMC10512413 DOI: 10.3389/fgene.2023.1252823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/15/2023] [Indexed: 09/26/2023] Open
Abstract
Objective: This retrospective study aims to evaluate the utility of exome sequencing (ES) in identifying genetic causes of congenital orofacial clefts (OFCs) in fetuses with or without other structural abnormalities, and to further explore congenital OFCs genetic causes. Methods: The study enrolled 107 singleton pregnancies diagnosed with fetal OFCs between January 2016 and May 2022, and categorized them into two groups: isolated cleft lip and/or palate (CL/CP) and syndromic CL/CP. Cases with positive karyotyping and chromosomal microarray analysis results were excluded. Whole-exome sequencing was performed on eligible fetuses and their parents. Monogenic variants identified by ES and perinatal outcomes were recorded and evaluated during postnatal follow-up. Results: Clinically significant variants were identified in 11.2% (12/107) of fetuses, with no significant difference in detection rate between the isolated CL/CP group and the syndromic CL/CP group (8/83, 9.6% vs. 4/24, 16.7%, p = 0.553). Additionally, sixteen (16/107, 15.0%) fetuses had variants of uncertain significance. We identified 12 clinically significant variations that correlated with clinical phenotypes in 11 genes from 12 fetuses, with CHD7 being the most frequently implicated gene (n = 2). Furthermore, we observed a significant difference in termination rates and survival rates between the isolated CL/CP and syndromic CL/CP groups (41.0% vs. 70.8% and 56.6% vs. 20.8%, p < 0.05 for both). Conclusion: Based on our findings, it is clear that ES provides a significant increase in diagnostic yield for the molecular diagnosis of congenital OFCs, thereby substantially improving the existing prenatal diagnostic capabilities. This study also sheds light on seven novel pathogenic variants, broadening our understanding of the genetic underpinnings of OFCs and expanding the disease spectrums of relevant genes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Can Liao
- Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
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14
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Xu J, Iyyanar PPR, Lan Y, Jiang R. Sonic hedgehog signaling in craniofacial development. Differentiation 2023; 133:60-76. [PMID: 37481904 PMCID: PMC10529669 DOI: 10.1016/j.diff.2023.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/04/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023]
Abstract
Mutations in SHH and several other genes encoding components of the Hedgehog signaling pathway have been associated with holoprosencephaly syndromes, with craniofacial anomalies ranging in severity from cyclopia to facial cleft to midfacial and mandibular hypoplasia. Studies in animal models have revealed that SHH signaling plays crucial roles at multiple stages of craniofacial morphogenesis, from cranial neural crest cell survival to growth and patterning of the facial primordia to organogenesis of the palate, mandible, tongue, tooth, and taste bud formation and homeostasis. This article provides a summary of the major findings in studies of the roles of SHH signaling in craniofacial development, with emphasis on recent advances in the understanding of the molecular and cellular mechanisms regulating the SHH signaling pathway activity and those involving SHH signaling in the formation and patterning of craniofacial structures.
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Affiliation(s)
- Jingyue Xu
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
| | - Paul P R Iyyanar
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Yu Lan
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Departments of Pediatrics and Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Rulang Jiang
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; Departments of Pediatrics and Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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15
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Onodera S, Azuma T. Hedgehog-Related Mutation Causes Bone Malformations with or without Hereditary Gene Mutations. Int J Mol Sci 2023; 24:12903. [PMID: 37629084 PMCID: PMC10454035 DOI: 10.3390/ijms241612903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/15/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
The hedgehog (Hh) family consists of numerous signaling mediators that play important roles at various stages of development. Thus, the Hh pathway is essential for bone tissue development and tumorigenesis. Gorlin syndrome is a skeletal and tumorigenic disorder caused by gain-of-function mutations in Hh signaling. In this review, we first present the phenotype of Gorlin syndrome and the relationship between genotype and phenotype in bone and craniofacial tissues, including the causative gene as well as other Hh-related genes. Next, the importance of new diagnostic methods using next-generation sequencing and multiple gene panels will be discussed. We summarize Hh-related genetic disorders, including cilia disease, and the genetics of Hh-related bone diseases.
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Affiliation(s)
- Shoko Onodera
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kanda Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan;
| | - Toshifumi Azuma
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kanda Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan;
- Oral Health Science Center, Tokyo Dental College, 2-9-18 Kanda Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan
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16
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Cheng C, Cong Q, Liu Y, Hu Y, Liang G, Dioneda KMM, Yang Y. Yap controls notochord formation and neural tube patterning by integrating mechanotransduction with FoxA2 and Shh expression. SCIENCE ADVANCES 2023; 9:eadf6927. [PMID: 37315133 PMCID: PMC10266736 DOI: 10.1126/sciadv.adf6927] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 05/04/2023] [Indexed: 06/16/2023]
Abstract
Correct notochord and neural tube (NT) formation is crucial to the development of the central nervous system and midline structures. Integrated biochemical and biophysical signaling controls embryonic growth and patterning; however, the underlying mechanisms remain poorly understood. Here, we took the opportunities of marked morphological changes during notochord and NT formation and identified both necessary and sufficient roles of Yap, a key mechanosensor and mechanotransducer, in biochemical signaling activation during formation of notochord and floor plate, the ventral signaling centers that pattern the dorsal-ventral axis of NT and the surrounding tissues. We showed that Yap activation by a gradient of mechanical stress and tissue stiffness in the notochord and ventral NT induces FoxA2 and Shh expression. Hedgehog signaling activation rescued NT patterning defects caused by Yap deficiency, but not notochord formation. Therefore, mechanotransduction via Yap activation acts in feedforward mechanisms to induce FoxA2 expression for notochord formation and activate Shh expression for floor plate induction by synergistically interacting with FoxA2.
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Affiliation(s)
| | | | - Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, 188 Longwood Ave., Boston, MA 02115, USA
| | - Yizhong Hu
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, 188 Longwood Ave., Boston, MA 02115, USA
| | - Guoyan Liang
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, 188 Longwood Ave., Boston, MA 02115, USA
| | - Kevin Marc Manquiquis Dioneda
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, 188 Longwood Ave., Boston, MA 02115, USA
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17
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Rai S, Leydier L, Sharma S, Katwala J, Sahu A. A quest for genetic causes underlying signaling pathways associated with neural tube defects. Front Pediatr 2023; 11:1126209. [PMID: 37284286 PMCID: PMC10241075 DOI: 10.3389/fped.2023.1126209] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/28/2023] [Indexed: 06/08/2023] Open
Abstract
Neural tube defects (NTDs) are serious congenital deformities of the nervous system that occur owing to the failure of normal neural tube closures. Genetic and non-genetic factors contribute to the etiology of neural tube defects in humans, indicating the role of gene-gene and gene-environment interaction in the occurrence and recurrence risk of neural tube defects. Several lines of genetic studies on humans and animals demonstrated the role of aberrant genes in the developmental risk of neural tube defects and also provided an understanding of the cellular and morphological programs that occur during embryonic development. Other studies observed the effects of folate and supplementation of folic acid on neural tube defects. Hence, here we review what is known to date regarding altered genes associated with specific signaling pathways resulting in NTDs, as well as highlight the role of various genetic, and non-genetic factors and their interactions that contribute to NTDs. Additionally, we also shine a light on the role of folate and cell adhesion molecules (CAMs) in neural tube defects.
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Affiliation(s)
- Sunil Rai
- Department of Molecular Biology, Medical University of the Americas, Charlestown, Saint Kitts and Nevis
| | - Larissa Leydier
- Department of Molecular Biology, Medical University of the Americas, Charlestown, Saint Kitts and Nevis
| | - Shivani Sharma
- Department of Molecular Biology, Medical University of the Americas, Charlestown, Saint Kitts and Nevis
| | - Jigar Katwala
- Department of Molecular Biology, Medical University of the Americas, Charlestown, Saint Kitts and Nevis
| | - Anurag Sahu
- Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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18
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Bulk J, Kyrychenko V, Rensinghoff PM, Ghaderi Ardekani Z, Heermann S. Holoprosencephaly with a Special Form of Anophthalmia Result from Experimental Induction of bmp4, Oversaturating BMP Antagonists in Zebrafish. Int J Mol Sci 2023; 24:ijms24098052. [PMID: 37175759 PMCID: PMC10178349 DOI: 10.3390/ijms24098052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Vision is likely our most prominent sense and a correct development of the eye is at its basis. Early eye development is tightly connected to the development of the forebrain. A single eye field and the prospective telencephalon are situated within the anterior neural plate (ANP). During normal development, both domains are split and consecutively, two optic vesicles and two telencephalic lobes emerge. If this process is hampered, the domains remain condensed at the midline. The resulting developmental disorder is termed holoprosencephaly (HPE). The typical ocular finding associated with intense forms of HPE is cyclopia. However, also anophthalmia and coloboma can be associated with HPE. Here, we report that a correct balance of Bone morphogenetic proteins (BMPs) and their antagonists are important for forebrain and eye field cleavage. Experimental induction of a BMP ligand results in a severe form of HPE showing anophthalmia. We identified a dysmorphic forebrain containing retinal progenitors, which we termed crypt-oculoid. Optic vesicle evagination is impaired due to a loss of rx3 and, consecutively, of cxcr4a. Our data further suggest that the subduction of prospective hypothalamic cells during neurulation and neural keel formation is affected by the induction of a BMP ligand.
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Affiliation(s)
- Johannes Bulk
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany
| | - Valentyn Kyrychenko
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany
| | - Philipp M Rensinghoff
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany
| | - Zahra Ghaderi Ardekani
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany
| | - Stephan Heermann
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany
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19
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Malta M, AlMutiri R, Martin CS, Srour M. Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management. CHILDREN 2023; 10:children10040647. [PMID: 37189898 DOI: 10.3390/children10040647] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/21/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.
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20
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Escuin S, Rose Raza-Knight S, Savery D, Gaston-Massuet C, Galea GL, Greene NDE, Copp AJ. Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse. Dis Model Mech 2023; 16:297163. [PMID: 36916392 PMCID: PMC10073009 DOI: 10.1242/dmm.049858] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 01/11/2023] [Indexed: 02/25/2023] Open
Abstract
Understanding the molecular mechanisms that lead to birth defects is an important step towards improved primary prevention. Mouse embryos homozygous for the Kumba (Ku) mutant allele of Zic2 develop severe spina bifida with complete lack of dorsolateral hinge points (DLHPs) in the neuroepithelium. Bone morphogenetic protein (BMP) signalling is overactivated in Zic2Ku/Ku embryos, and the BMP inhibitor dorsomorphin partially rescues neural tube closure in cultured embryos. RhoA signalling is also overactivated, with accumulation of actomyosin in the Zic2Ku/Ku neuroepithelium, and the myosin inhibitor Blebbistatin partially normalises neural tube closure. However, dorsomorphin and Blebbistatin differ in their effects at tissue and cellular levels: DLHP formation is rescued by dorsomorphin but not Blebbistatin, whereas abnormal accumulation of actomyosin is rescued by Blebbistatin but not dorsomorphin. These findings suggest a dual mechanism of spina bifida origin in Zic2Ku/Ku embryos: faulty BMP-dependent formation of DLHPs and RhoA-dependent F-actin accumulation in the neuroepithelium. Hence, we identify a multi-pathway origin of spina bifida in a mammalian system that may provide a developmental basis for understanding the corresponding multifactorial human defects.
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Affiliation(s)
- Sarah Escuin
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
| | - Saba Rose Raza-Knight
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
| | - Dawn Savery
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
| | - Carles Gaston-Massuet
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
| | - Gabriel L Galea
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
| | - Nicholas D E Greene
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
| | - Andrew J Copp
- Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
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21
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Dilower I, Niloy AJ, Kumar V, Kothari A, Lee EB, Rumi MAK. Hedgehog Signaling in Gonadal Development and Function. Cells 2023; 12:358. [PMID: 36766700 PMCID: PMC9913308 DOI: 10.3390/cells12030358] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/14/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Three distinct hedgehog (HH) molecules, (sonic, desert, and indian), two HH receptors (PTCH1 and PTCH2), a membrane bound activator (SMO), and downstream three transcription factors (GLI1, GLI2, and GLI3) are the major components of the HH signaling. These signaling molecules were initially identified in Drosophila melanogaster. Later, it has been found that the HH system is highly conserved across species and essential for organogenesis. HH signaling pathways play key roles in the development of the brain, face, skeleton, musculature, lungs, and gastrointestinal tract. While the sonic HH (SHH) pathway plays a major role in the development of the central nervous system, the desert HH (DHH) regulates the development of the gonads, and the indian HH (IHH) acts on the development of bones and joints. There are also overlapping roles among the HH molecules. In addition to the developmental role of HH signaling in embryonic life, the pathways possess vital physiological roles in testes and ovaries during adult life. Disruption of DHH and/or IHH signaling results in ineffective gonadal steroidogenesis and gametogenesis. While DHH regulates the male gonadal functions, ovarian functions are regulated by both DHH and IHH. This review article focuses on the roles of HH signaling in gonadal development and reproductive functions with an emphasis on ovarian functions. We have acknowledged the original research work that initially reported the findings and discussed the subsequent studies that have further analyzed the role of HH signaling in testes and ovaries.
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Affiliation(s)
| | | | | | | | | | - M. A. Karim Rumi
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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22
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Chattopadhyay A, Sharma A. Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis. Front Mol Biosci 2023; 10:1120373. [PMID: 36714259 PMCID: PMC9878332 DOI: 10.3389/fmolb.2023.1120373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
The biosynthesis of cholesterol, an essential component of higher eukaryotic membranes, was worked out by Konrad Bloch (and Feodor Lynen) in the 1960s and they received the Nobel Prize around that time in recognition of their pioneering contributions. An elegant consequence of this was a hypothesis proposed by Konrad Bloch (the Bloch hypothesis) which suggests that each subsequent intermediate in the cholesterol biosynthesis pathway is superior in supporting membrane function in higher eukaryotes relative to its precursor. In this review, we discuss an autosomal recessive metabolic disorder, known as Smith-Lemli-Opitz syndrome (SLOS), associated with a defect in the Kandutsch-Russell pathway of cholesterol biosynthesis that results in accumulation of the immediate precursor of cholesterol in its biosynthetic pathway (7-dehydrocholesterol) and an altered cholesterol to total sterol ratio. Patients suffering from SLOS have several developmental, behavioral and cognitive abnormalities for which no drug is available yet. We characterize SLOS as a manifestation of the Bloch hypothesis and review its molecular etiology and current treatment. We further discuss defective Hedgehog signaling in SLOS and focus on the role of the serotonin1A receptor, a representative neurotransmitter receptor belonging to the GPCR family, in SLOS. Notably, ligand binding activity and cellular signaling of serotonin1A receptors are impaired in SLOS-like condition. Importantly, cellular localization and intracellular trafficking of the serotonin1A receptor (which constitute an important determinant of a GPCR cellular function) are compromised in SLOS. We highlight some of the recent developments and emerging concepts in SLOS pathobiology and suggest that novel therapies based on trafficking defects of target receptors could provide new insight into treatment of SLOS.
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Affiliation(s)
- Amitabha Chattopadhyay
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India,Academy of Scientific and Innovative Research, Ghaziabad, India,*Correspondence: Amitabha Chattopadhyay,
| | - Ashwani Sharma
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India,Academy of Scientific and Innovative Research, Ghaziabad, India
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23
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Lipinski RJ, Krauss RS. Gene-environment interactions in birth defect etiology: Challenges and opportunities. Curr Top Dev Biol 2023; 152:1-30. [PMID: 36707208 PMCID: PMC9942595 DOI: 10.1016/bs.ctdb.2022.10.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Birth defects are relatively common congenital outcomes that significantly impact affected individuals, their families, and communities. Effective development and deployment of prevention and therapeutic strategies for these conditions requires sufficient understanding of etiology, including underlying genetic and environmental causes. Tremendous progress has been made in defining the genetic basis of familial and syndromic forms of birth defects. However, the majority of birth defect cases are considered nonsyndromic and thought to result from multifactorial gene-environment interactions. While substantial advances have been made in elucidating the genetic landscape of these etiologically complex conditions, significant biological and technical constraints have stymied progress toward a refined knowledge of environmental risk factors. Defining specific gene-environment interactions in birth defect etiology is even more challenging. However, progress has been made, including demonstration of critical proofs of concept and development of new conceptual and technical approaches for resolving complex gene-environment interactions. In this review, we discuss current views of multifactorial birth defect etiology, comparing them with other diseases that also involve gene-environment interactions, including primary immunodeficiency and cancer. We describe how various model systems have illuminated mechanisms of multifactorial etiology and these models' individual strengths and weaknesses. Finally, suggestions for areas of future emphasis are proposed.
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Affiliation(s)
- Robert J. Lipinski
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, United States,Corresponding authors: ;
| | - Robert S. Krauss
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States,Corresponding authors: ;
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24
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Sonawala K, Ramalingam S, Sellamuthu I. Influence of Long Non-Coding RNA in the Regulation of Cancer Stem Cell Signaling Pathways. Cells 2022; 11:3492. [PMID: 36359888 PMCID: PMC9656902 DOI: 10.3390/cells11213492] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 08/03/2023] Open
Abstract
Over the past two decades, cancer stem cells (CSCs) have emerged as an immensely studied and experimental topic, however a wide range of questions concerning the topic still remain unanswered; in particular, the mechanisms underlying the regulation of tumor stem cells and their characteristics. Understanding the cancer stem-cell signaling pathways may pave the way towards a better comprehension of these mechanisms. Signaling pathways such as WNT, STAT, Hedgehog, NOTCH, PI3K/AKT/mTOR, TGF-β, and NF-κB are responsible not only for modulating various features of CSCs but also their microenvironments. Recently, the prominent roles of various non-coding RNAs such as small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) in developing and enhancing the tumor phenotypes have been unfolded. This review attempts to shed light on understanding the influence of long non- coding RNAs in the modulation of various CSC-signaling pathways and its impact on the CSCs and tumor properties; highlighting the protagonistic and antagonistic roles of lncRNAs.
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Affiliation(s)
| | | | - Iyappan Sellamuthu
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chennai 603202, India
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25
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He Q, Hao X, Bao S, Wu X, Xu L, Hou Y, Huang Y, Peng L, Huang H, Ding Y, Zhao H. A392V and R945X mutations cause orofacial clefts via impairing PTCH1 function. Genomics 2022; 114:110507. [PMID: 36265746 DOI: 10.1016/j.ygeno.2022.110507] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 09/30/2022] [Accepted: 10/16/2022] [Indexed: 01/15/2023]
Abstract
The Hedgehog (HH) signaling plays key roles in embryogenesis and organogenesis, and its dysfunction causes a variety of human birth defects. Orofacial cleft (OFC) is one of the most common congenital craniofacial defects, and its etiology is closely related to mutations in multiple components in the HH pathway, including the PTCH1 receptor. A quantity of PTCH1 variants have been associated with OFC, but the pathogenicity and underlying mechanism of these variants have not been functionally validated. In our previous studies, we identified two PTCH1 variants (A392V and R945X) in two families with hereditary OFC. Here we explore the functional consequences of these two variants. In zebrafish embryos, microinjection of wild type PTCH1 mRNA causes curved body axis and craniofacial anomalies. In contrast, microinjection of A392V and R945X PTCH1 mRNAs results in much milder phenotypes, suggesting these two variants are loss-of-function mutations. In mammalian cells, A392V and R945X mutations reverse the inhibitory effect of PTCH1 on HH signaling. Biochemically, the two mutants PTCH1 show lower expression levels and shortened half-life, indicting these mutations decrease the stability of PTCH1. A392V and R945X mutations also appear to cause PTCH1 to localize away from vesicles. Taken together, our findings indicate that A392V and R945X variants are loss-of-function mutations that disrupt the function of PTCH1 and thus cause dysregulation of HH signaling, leading to the pathogenesis of OFC.
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Affiliation(s)
- Qing He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Xingke Hao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Shanying Bao
- Department of Stomatology, Affiliated Hospital of Qinghai University, Xining, Qinghai, PR China
| | - Xiantao Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Linping Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Yuxia Hou
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China; Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Yingjia Huang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Leiyuan Peng
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Huimei Huang
- Department of Nephrology, Xi'an Children's Hospital, The Affiliated Children's Hospital of Xi'an Jiaotong University, PR China.
| | - Yi Ding
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
| | - Huaxiang Zhao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China; Department of Orthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
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26
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Wang J, Ware K, Bedolla A, Allgire E, Turcato FC, Weed M, Sah R, Luo Y. Disruption of Sonic Hedgehog Signaling Accelerates Age-Related Neurogenesis Decline and Abolishes Stroke-Induced Neurogenesis and Leads to Increased Anxiety Behavior in Stroke Mice. Transl Stroke Res 2022; 13:830-844. [PMID: 35146631 PMCID: PMC10114538 DOI: 10.1007/s12975-022-00994-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/10/2022] [Accepted: 01/31/2022] [Indexed: 02/03/2023]
Abstract
Sonic Hedgehog (SHH) signaling has a critical role in mediating developmental neurogenesis and has been implicated in adult subventricular (SVZ) neurogenesis. However, the precise role of Smoothened (SMO) receptor-mediated SHH signaling in adult neurogenesis during aging especially in hippocampal subgranular zone (SGZ) neurogenesis remains undefined. Additionally, our previous study showed that stimulation of SHH signaling post-stroke leads to increased neurogenesis and improved behavioral functions after stroke. However, it is not clear whether SHH signaling in neural stem cells (NSCs) is required for stroke-induced neurogenesis and functional recovery post-stroke. In this study, using conditional knockout (cKO) of SHH signaling receptor Smo gene in NSCs, we show a decreased neurogenesis at both SVZ and SGZ in young-adult mice and an accelerated depletion of neurogenic cells in the process of aging suggesting that SHH signaling is critical in maintaining neurogenesis during aging. Behavior studies revealed that compromised neurogenesis in Smo cKO mice leads to increased anxiety/depression-like behaviors without affecting general locomotor function or spatial and fear-related learning. Importantly, we also show that NSCs with a cKO of SHH signaling abolishes stroke-induced neurogenesis in Smo cKO mice. Compared to control mice, Smo cKO mice also show delayed motor function recovery and increased anxiety level after stroke. Our data highlights the essential role of Smo function in regulating adult neurogenesis and emotional behaviors during both aging and CNS injury such as stroke.
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Affiliation(s)
- Jiapeng Wang
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA
- Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Kierra Ware
- Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Alicia Bedolla
- Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Emily Allgire
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
- Department of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Flavia Correa Turcato
- Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Maxwell Weed
- Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Renu Sah
- Neuroscience Graduate Program, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA
- Department of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, OH, 45267, USA
- Cincinnati VA Medical Center, Cincinnati, OH, 45220, USA
| | - Yu Luo
- Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
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Krueger LA, Morris AC. Eyes on CHARGE syndrome: Roles of CHD7 in ocular development. Front Cell Dev Biol 2022; 10:994412. [PMID: 36172288 PMCID: PMC9512043 DOI: 10.3389/fcell.2022.994412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/19/2022] [Indexed: 11/13/2022] Open
Abstract
The development of the vertebrate visual system involves complex morphogenetic interactions of cells derived from multiple embryonic lineages. Disruptions in this process are associated with structural birth defects such as microphthalmia, anophthalmia, and coloboma (collectively referred to as MAC), and inherited retinal degenerative diseases such as retinitis pigmentosa and allied dystrophies. MAC and retinal degeneration are also observed in systemic congenital malformation syndromes. One important example is CHARGE syndrome, a genetic disorder characterized by coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Mutations in the gene encoding Chromodomain helicase DNA binding protein 7 (CHD7) cause the majority of CHARGE syndrome cases. However, the pathogenetic mechanisms that connect loss of CHD7 to the ocular complications observed in CHARGE syndrome have not been identified. In this review, we provide a general overview of ocular development and congenital disorders affecting the eye. This is followed by a comprehensive description of CHARGE syndrome, including discussion of the spectrum of ocular defects that have been described in this disorder. In addition, we discuss the current knowledge of CHD7 function and focus on its contributions to the development of ocular structures. Finally, we discuss outstanding gaps in our knowledge of the role of CHD7 in eye formation, and propose avenues of investigation to further our understanding of how CHD7 activity regulates ocular and retinal development.
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Affiliation(s)
| | - Ann C. Morris
- Department of Biology, University of Kentucky, Lexington, KY, United States
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28
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Canonical Hedgehog Pathway and Noncanonical GLI Transcription Factor Activation in Cancer. Cells 2022; 11:cells11162523. [PMID: 36010600 PMCID: PMC9406872 DOI: 10.3390/cells11162523] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 01/12/2023] Open
Abstract
The Hedgehog signaling pathway is one of the fundamental pathways required for development and regulation of postnatal regeneration in a variety of tissues. The pathway has also been associated with cancers since the identification of a mutation in one of its components, PTCH, as the cause of Basal Cell Nevus Syndrome, which is associated with several cancers. Our understanding of the pathway in tumorigenesis has expanded greatly since that initial discovery over two decades ago. The pathway has tumor-suppressive and oncogenic functions depending on the context of the cancer. Furthermore, noncanonical activation of GLI transcription factors has been reported in a number of tumor types. Here, we review the roles of canonical Hedgehog signaling pathway and noncanonical GLI activation in cancers, particularly epithelial cancers, and discuss an emerging concept of the distinct outcomes that these modes have on cancer initiation and progression.
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29
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Lu F, Ferriero DM, Jiang X. Cholesterol in Brain Development and Perinatal Brain Injury: More than a Building Block. Curr Neuropharmacol 2022; 20:1400-1412. [PMID: 34766894 PMCID: PMC9881076 DOI: 10.2174/1570159x19666211111122311] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/21/2021] [Accepted: 10/06/2021] [Indexed: 11/22/2022] Open
Abstract
The central nervous system (CNS) is enriched with important classes of lipids, in which cholesterol is known to make up a major portion of myelin sheaths, besides being a structural and functional unit of CNS cell membranes. Unlike in the adult brain, where the cholesterol pool is relatively stable, cholesterol is synthesized and accumulated at the highest rate in the developing brain to meet the needs of rapid brain growth at this stage, which is also a critical period for neuroplasticity. In addition to its biophysical role in membrane organization, cholesterol is crucial for brain development due to its involvement in brain patterning, myelination, neuronal differentiation, and synaptogenesis. Thus any injuries to the immature brain that affect cholesterol homeostasis may have long-term adverse neurological consequences. In this review, we describe the unique features of brain cholesterol biosynthesis and metabolism, cholesterol trafficking between different cell types, and highlight cholesterol-dependent biological processes during brain maturation. We also discuss the association of impaired cholesterol homeostasis with several forms of perinatal brain disorders in term and preterm newborns, including hypoxic-ischemic encephalopathy. Strategies targeting the cholesterol pathways may open new avenues for the diagnosis and treatment of developmental brain injury.
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Affiliation(s)
- Fuxin Lu
- Departments of Neurology, University of California San Francisco, San Francisco, CA, USA;
| | - Donna M. Ferriero
- Departments of Neurology, University of California San Francisco, San Francisco, CA, USA; ,Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA
| | - Xiangning Jiang
- Departments of Neurology, University of California San Francisco, San Francisco, CA, USA; ,Address correspondence to this author at the Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane Room 494, San Francisco, CA 94158, USA; Tel/Fax: 415-502-7285; E-mail:
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30
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Novel Genetic Diagnoses in Septo-Optic Dysplasia. Genes (Basel) 2022; 13:genes13071165. [PMID: 35885948 PMCID: PMC9320703 DOI: 10.3390/genes13071165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 12/04/2022] Open
Abstract
Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia.
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31
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Brain Organization and Human Diseases. Cells 2022; 11:cells11101642. [PMID: 35626679 PMCID: PMC9139716 DOI: 10.3390/cells11101642] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/09/2022] [Accepted: 05/12/2022] [Indexed: 02/06/2023] Open
Abstract
The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common cortical malformations and their manifestation in the human brain.
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32
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Aniridia-related keratopathy relevant cell signaling pathways in human fetal corneas. Histochem Cell Biol 2022; 158:169-180. [PMID: 35551459 PMCID: PMC9338123 DOI: 10.1007/s00418-022-02099-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2022] [Indexed: 11/26/2022]
Abstract
We aimed to study aniridia-related keratopathy (ARK) relevant cell signaling pathways [Notch1, Wnt/β-catenin, Sonic hedgehog (SHH) and mTOR] in normal human fetal corneas compared with normal human adult corneas and ARK corneas. We found that fetal corneas at 20 weeks of gestation (wg) and normal adult corneas showed similar staining patterns for Notch1; however 10–11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared with the adult corneas. Fetal corneas showed stronger immunolabeling with antibodies against β-catenin, Wnt5a, Wnt7a, Gli1, Hes1, p-rpS6, and mTOR when compared with the adult corneas. Gene expression of Notch1, Wnt5A, Wnt7A, β-catenin, Hes1, mTOR, and rps6 was higher in the 9–12 wg fetal corneas compared with adult corneas. The cell signaling pathway differences found between human fetal and adult corneas were similar to those previously found in ARK corneas with the exception of Notch1. Analogous profiles of cell signaling pathway activation between human fetal corneas and ARK corneas suggests that there is a less differentiated host milieu in ARK.
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33
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Guo Y, Wu D, Xu Q, Chen W. Inhibition of smoothened receptor by vismodegib leads to micrognathia during embryogenesis. Differentiation 2022; 125:27-34. [DOI: 10.1016/j.diff.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/03/2022] [Accepted: 04/07/2022] [Indexed: 11/03/2022]
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34
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Chua EHZ, Yasar S, Harmston N. The importance of considering regulatory domains in genome-wide analyses - the nearest gene is often wrong! Biol Open 2022; 11:274931. [PMID: 35377406 PMCID: PMC9002814 DOI: 10.1242/bio.059091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The expression of a large number of genes is regulated by regulatory elements that are located far away from their promoters. Identifying which gene is the target of a specific regulatory element or is affected by a non-coding mutation is often accomplished by assigning these regions to the nearest gene in the genome. However, this heuristic ignores key features of genome organisation and gene regulation; in that the genome is partitioned into regulatory domains, which at some loci directly coincide with the span of topologically associated domains (TADs), and that genes are regulated by enhancers located throughout these regions, even across intervening genes. In this review, we examine the results from genome-wide studies using chromosome conformation capture technologies and from those dissecting individual gene regulatory domains, to highlight that the phenomenon of enhancer skipping is pervasive and affects multiple types of genes. We discuss how simply assigning a genomic region of interest to its nearest gene is problematic and often leads to incorrect predictions and highlight that where possible information on both the conservation and topological organisation of the genome should be used to generate better hypotheses. The article has an associated Future Leader to Watch interview. Summary: Identifying which gene is the target of an enhancer is often accomplished by assigning it to the nearest gene, here we discuss how this heuristic can lead to incorrect predictions.
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Affiliation(s)
| | - Samen Yasar
- Science Division, Yale-NUS College, Singapore 138527, Singapore
| | - Nathan Harmston
- Science Division, Yale-NUS College, Singapore 138527, Singapore.,Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore
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35
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Nian FS, Hou PS. Evolving Roles of Notch Signaling in Cortical Development. Front Neurosci 2022; 16:844410. [PMID: 35422684 PMCID: PMC9001970 DOI: 10.3389/fnins.2022.844410] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/15/2022] [Indexed: 01/09/2023] Open
Abstract
Expansion of the neocortex is thought to pave the way toward acquisition of higher cognitive functions in mammals. The highly conserved Notch signaling pathway plays a crucial role in this process by regulating the size of the cortical progenitor pool, in part by controlling the balance between self-renewal and differentiation. In this review, we introduce the components of Notch signaling pathway as well as the different mode of molecular mechanisms, including trans- and cis-regulatory processes. We focused on the recent findings with regard to the expression pattern and levels in regulating neocortical formation in mammals and its interactions with other known signaling pathways, including Slit–Robo signaling and Shh signaling. Finally, we review the functions of Notch signaling pathway in different species as well as other developmental process, mainly somitogenesis, to discuss how modifications to the Notch signaling pathway can drive the evolution of the neocortex.
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Affiliation(s)
- Fang-Shin Nian
- Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Shan Hou
- Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- *Correspondence: Pei-Shan Hou,
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36
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Boyling A, Perez-Siles G, Kennerson ML. Structural Variation at a Disease Mutation Hotspot: Strategies to Investigate Gene Regulation and the 3D Genome. Front Genet 2022; 13:842860. [PMID: 35401663 PMCID: PMC8990796 DOI: 10.3389/fgene.2022.842860] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/21/2022] [Indexed: 12/18/2022] Open
Abstract
A rare form of X-linked Charcot-Marie-Tooth neuropathy, CMTX3, is caused by an interchromosomal insertion occurring at chromosome Xq27.1. Interestingly, eight other disease phenotypes have been associated with insertions (or insertion-deletions) occurring at the same genetic locus. To date, the pathogenic mechanism underlying most of these diseases remains unsolved, although local gene dysregulation has clearly been implicated in at least two phenotypes. The challenges of accessing disease-relevant tissue and modelling these complex genomic rearrangements has led to this research impasse. We argue that recent technological advancements can overcome many of these challenges, particularly induced pluripotent stem cells (iPSC) and their capacity to provide access to patient-derived disease-relevant tissue. However, to date these valuable tools have not been utilized to investigate the disease-associated insertions at chromosome Xq27.1. Therefore, using CMTX3 as a reference disease, we propose an experimental approach that can be used to explore these complex mutations, as well as similar structural variants located elsewhere in the genome. The mutational hotspot at Xq27.1 is a valuable disease paradigm with the potential to improve our understanding of the pathogenic consequences of complex structural variation, and more broadly, refine our knowledge of the multifaceted process of long-range gene regulation. Intergenic structural variation is a critically understudied class of mutation, although it is likely to contribute significantly to unsolved genetic disease.
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Affiliation(s)
- Alexandra Boyling
- Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia
- *Correspondence: Alexandra Boyling, ; Marina L. Kennerson,
| | - Gonzalo Perez-Siles
- Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Marina L. Kennerson
- Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia
- Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia
- *Correspondence: Alexandra Boyling, ; Marina L. Kennerson,
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37
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Tingler M, Philipp M, Burkhalter MD. DNA Replication proteins in primary microcephaly syndromes. Biol Cell 2022; 114:143-159. [PMID: 35182397 DOI: 10.1111/boc.202100061] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 11/30/2022]
Abstract
SCOPE Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. It is characterized by a reduced head circumference, which correlates with a reduction in brain size. This often corresponds to a general underdevelopment of the brain and entails cognitive, behavioral and motoric retardation. In the past decade significant research efforts have been undertaken to identify genes and the molecular mechanisms underlying microcephaly. One such gene set encompasses factors required for DNA replication. Intriguingly, a growing body of evidence indicates that a substantial number of these genes mediate faithful centrosome and cilium function in addition to their canonical function in genome duplication. Here, we summarize, which DNA replication factors are associated with microcephaly syndromes and to which extent they impact on centrosomes and cilia. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Melanie Tingler
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, 72074, Germany
| | - Melanie Philipp
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, 72074, Germany
| | - Martin D Burkhalter
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University Tübingen, Tübingen, 72074, Germany
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38
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Barratt KS, Drover KA, Thomas ZM, Arkell RM. Patterning of the antero-ventral mammalian brain: Lessons from holoprosencephaly comparative biology in man and mouse. WIREs Mech Dis 2022; 14:e1552. [PMID: 35137563 DOI: 10.1002/wsbm.1552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/30/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
Adult form and function are dependent upon the activity of specialized signaling centers that act early in development at the embryonic midline. These centers instruct the surrounding cells to adopt a positional fate and to form the patterned structures of the phylotypic embryo. Abnormalities in these processes have devastating consequences for the individual, as exemplified by holoprosencephaly in which anterior midline development fails, leading to structural defects of the brain and/or face. In the 25 years since the first association between human holoprosencephaly and the sonic hedgehog gene, a combination of human and animal genetic studies have enhanced our understanding of the genetic and embryonic causation of this congenital defect. Comparative biology has extended the holoprosencephaly network via the inclusion of gene mutations from multiple signaling pathways known to be required for anterior midline formation. It has also clarified aspects of holoprosencephaly causation, showing that it arises when a deleterious variant is present within a permissive genome, and that environmental factors, as well as embryonic stochasticity, influence the phenotypic outcome of the variant. More than two decades of research can now be distilled into a framework of embryonic and genetic causation. This framework means we are poised to move beyond our current understanding of variants in signaling pathway molecules. The challenges now at the forefront of holoprosencephaly research include deciphering how the mutation of genes involved in basic cell processes can also cause holoprosencephaly, determining the important constituents of the holoprosencephaly permissive genome, and identifying environmental compounds that promote holoprosencephaly. This article is categorized under: Congenital Diseases > Stem Cells and Development Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Molecular and Cellular Physiology Congenital Diseases > Environmental Factors.
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Affiliation(s)
- Kristen S Barratt
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Kyle A Drover
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Zoe M Thomas
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Ruth M Arkell
- John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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39
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Zhong C, Wang B. Regulation of Cholesterol Binding to the Receptor Patched1 by its interactions With the Ligand Sonic Hedgehog (Shh). Front Mol Biosci 2022; 9:831891. [PMID: 35187087 PMCID: PMC8847689 DOI: 10.3389/fmolb.2022.831891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/11/2022] [Indexed: 01/17/2023] Open
Abstract
The Hedgehog (Hh) signaling pathway is essential in cell development and regeneration, which is activated by the ligand Sonic hedgehog (Shh). The binding of Shh to its receptor Patched1 (PTCH1) releases the inhibitory effect on the downstream protein Smoothened (SMO), a G-protein-coupled-receptor (GPCR) protein. Cholesterol was supposed to function as a secondary messenger between PTCH1 and SMO. However, the molecular mechanism of this regulation process is still unclear. Therefore, microsecond coarse-grained molecular dynamics simulations were performed to investigate the protein-lipid interactions of the PTCH1 monomer and dimer-Shh complex. It was observed that the binding of cholesterols to the monomer is more stable than that to the dimer-Shh complex. It is regulated by the enrichment of Ganglioside lipids around proteins and the conformation of Y446, a residue in the sterol-sensing domain (SSD). The regulation of Shh on the dynamics of PTCH1 was further analyzed to explore the allosteric communication pathways between the Shh and the SSD. Our study provides structural and dynamic details of an additional perspective on the regulation of Hh signaling pathway through the lipid micro-environments of PTCH1.
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Affiliation(s)
- Changqing Zhong
- Centre for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Beibei Wang
- Centre for Advanced Materials Research, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, China
- *Correspondence: Beibei Wang,
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40
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Lo HF, Hong M, Krauss RS. Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly. Front Cell Dev Biol 2022; 9:795194. [PMID: 35004690 PMCID: PMC8727999 DOI: 10.3389/fcell.2021.795194] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/29/2021] [Indexed: 12/17/2022] Open
Abstract
Many common developmental disorders are thought to arise from a complex set of genetic and environmental risk factors. These factors interact with each other to affect the strength and duration of key developmental signaling pathways, thereby increasing the possibility that they fail to achieve the thresholds required for normal embryonic patterning. One such disorder, holoprosencephaly (HPE), serves as a useful model system in understanding various forms of multifactorial etiology. Genomic analysis of HPE cases, epidemiology, and mechanistic studies of animal models have illuminated multiple potential ways that risk factors interact to produce adverse developmental outcomes. Among these are: 1) interactions between driver and modifier genes; 2) oligogenic inheritance, wherein each parent provides predisposing variants in one or multiple distinct loci; 3) interactions between genetic susceptibilities and environmental risk factors that may be insufficient on their own; and 4) interactions of multiple genetic variants with multiple non-genetic risk factors. These studies combine to provide concepts that illuminate HPE and are also applicable to additional disorders with complex etiology, including neural tube defects, congenital heart defects, and oro-facial clefting.
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Affiliation(s)
- Hsiao-Fan Lo
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Mingi Hong
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Robert S Krauss
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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41
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Plaza-Diaz J, Izquierdo D, Torres-Martos Á, Baig AT, Aguilera CM, Ruiz-Ojeda FJ. Impact of Physical Activity and Exercise on the Epigenome in Skeletal Muscle and Effects on Systemic Metabolism. Biomedicines 2022; 10:biomedicines10010126. [PMID: 35052805 PMCID: PMC8773693 DOI: 10.3390/biomedicines10010126] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 12/30/2021] [Accepted: 01/04/2022] [Indexed: 02/05/2023] Open
Abstract
Exercise and physical activity induces physiological responses in organisms, and adaptations in skeletal muscle, which is beneficial for maintaining health and preventing and/or treating most chronic diseases. These adaptations are mainly instigated by transcriptional responses that ensue in reaction to each individual exercise, either resistance or endurance. Consequently, changes in key metabolic, regulatory, and myogenic genes in skeletal muscle occur as both an early and late response to exercise, and these epigenetic modifications, which are influenced by environmental and genetic factors, trigger those alterations in the transcriptional responses. DNA methylation and histone modifications are the most significant epigenetic changes described in gene transcription, linked to the skeletal muscle transcriptional response to exercise, and mediating the exercise adaptations. Nevertheless, other alterations in the epigenetics markers, such as epitranscriptomics, modifications mediated by miRNAs, and lactylation as a novel epigenetic modification, are emerging as key events for gene transcription. Here, we provide an overview and update of the impact of exercise on epigenetic modifications, including the well-described DNA methylations and histone modifications, and the emerging modifications in the skeletal muscle. In addition, we describe the effects of exercise on epigenetic markers in other metabolic tissues; also, we provide information about how systemic metabolism or its metabolites influence epigenetic modifications in the skeletal muscle.
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Affiliation(s)
- Julio Plaza-Diaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain; (D.I.); (C.M.A.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain;
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada;
- Correspondence: (J.P.-D.); (F.J.R.-O.); Tel.: +34-9-5824-1000 (ext. 20314) (F.J.R.-O.)
| | - David Izquierdo
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain; (D.I.); (C.M.A.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain;
| | - Álvaro Torres-Martos
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain;
| | - Aiman Tariq Baig
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada;
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 85M, Canada
| | - Concepción M. Aguilera
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain; (D.I.); (C.M.A.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain;
- Center of Biomedical Research, Institute of Nutrition and Food Technology “José Mataix”, University of Granada, Avda. del Conocimiento s/n., 18016 Granada, Spain
- CIBEROBN (CIBER Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Francisco Javier Ruiz-Ojeda
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain; (D.I.); (C.M.A.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain;
- RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz, Center Munich, Neuherberg, 85764 Munich, Germany
- Correspondence: (J.P.-D.); (F.J.R.-O.); Tel.: +34-9-5824-1000 (ext. 20314) (F.J.R.-O.)
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Fan LL, Sheng Y, Wang CY, Li YL, Liu JS. Case Report: Congenital Brain Dysplasia, Developmental Delay and Intellectual Disability in a Patient With a 7q35-7q36.3 Deletion. Front Genet 2021; 12:761003. [PMID: 34925452 PMCID: PMC8671813 DOI: 10.3389/fgene.2021.761003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/05/2021] [Indexed: 11/13/2022] Open
Abstract
7q terminal deletion syndrome is a rare condition presenting with multiple congenital malformations, including abnormal brain and facial structures, developmental delay, intellectual disability, abnormal limbs, and sacral anomalies. At least 40 OMIM genes located in the 7q34-7q36.3 region act as candidate genes for these phenotypes, of which SHH, EN2, KCNH2, RHEB, HLXB9, EZH2, MNX1 and LIMR1 may be the most important. In this study, we discuss the case of a 2.5-year-old male patient with multiple malformations, congenital brain dysplasia, developmental delay, and intellectual disability. A high-resolution genome-wide single nucleotide polymorphism array and real-time polymerase chain reaction were performed to detect genetic lesions. A de novo 9.4 Mb deletion in chromosome region 7q35-7q36.3 (chr7:147,493,985-156,774,460) was found. This chromosome region contains 68 genes, some of which are candidate genes for each phenotype. To the best of our knowledge, this is a rare case report of 7q terminal deletion syndrome in a Chinese patient. Our study identifies a rare phenotype in terms of brain structure abnormalities and cerebellar sulcus widening in patients with deletion in 7q35-7q36.3.
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Affiliation(s)
- Liang-Liang Fan
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha, China.,Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, China.,Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, China
| | - Yue Sheng
- Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, China
| | - Chen-Yu Wang
- Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, China
| | - Ya-Li Li
- Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, China
| | - Ji-Shi Liu
- Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, China
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Patel TN, Dhanyamraju PK. Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies. J Biomed Res 2021; 36:1-9. [PMID: 34963676 PMCID: PMC8894283 DOI: 10.7555/jbr.35.20210139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Development is a sophisticated process maintained by various signal transduction pathways, including the Hedgehog (Hh) pathway. Several important functions are executed by the Hh signaling cascade such as organogenesis, tissue regeneration, and tissue homeostasis, among various others. Considering the multiple functions carried out by this pathway, any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers. In the present review article, we explored a wide range of diseases caused by aberrant Hh signaling, including developmental defects and cancers. Finally, we concluded this mini-review with various treatment strategies for Hh-induced diseases.
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Affiliation(s)
- Trupti N Patel
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Vellore, Tamil Nadu 632014, India
| | - Pavan Kumar Dhanyamraju
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.,Penn State Cancer Institute, Hershey, PA 17033, USA
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44
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Molecular Bases of Human Malformation Syndromes Involving the SHH Pathway: GLIA/R Balance and Cardinal Phenotypes. Int J Mol Sci 2021; 22:ijms222313060. [PMID: 34884862 PMCID: PMC8657641 DOI: 10.3390/ijms222313060] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 11/27/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022] Open
Abstract
Human hereditary malformation syndromes are caused by mutations in the genes of the signal transduction molecules involved in fetal development. Among them, the Sonic hedgehog (SHH) signaling pathway is the most important, and many syndromes result from its disruption. In this review, we summarize the molecular mechanisms and role in embryonic morphogenesis of the SHH pathway, then classify the phenotype of each malformation syndrome associated with mutations of major molecules in the pathway. The output of the SHH pathway is shown as GLI activity, which is generated by SHH in a concentration-dependent manner, i.e., the sum of activating form of GLI (GLIA) and repressive form of GLI (GLIR). Which gene is mutated and whether the mutation is loss-of-function or gain-of-function determine in which concentration range of SHH the imbalance occurs. In human malformation syndromes, too much or too little GLI activity produces symmetric phenotypes affecting brain size, craniofacial (midface) dysmorphism, and orientation of polydactyly with respect to the axis of the limb. The symptoms of each syndrome can be explained by the GLIA/R balance model.
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45
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Marczenke M, Sunaga-Franze DY, Popp O, Althaus IW, Sauer S, Mertins P, Christ A, Allen BL, Willnow TE. GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. Development 2021; 148:272617. [PMID: 34698766 PMCID: PMC8627604 DOI: 10.1242/dev.200080] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022]
Abstract
Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations.
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Affiliation(s)
- Maike Marczenke
- Molecular Physiology, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.,Department of Biology, Chemistry and Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany
| | | | - Oliver Popp
- Proteomics Platform, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Irene W Althaus
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sascha Sauer
- Genomics Platform, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Philipp Mertins
- Proteomics Platform, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Annabel Christ
- Molecular Physiology, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Benjamin L Allen
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Thomas E Willnow
- Molecular Physiology, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.,Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
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46
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Garcia-Bonilla M, McAllister JP, Limbrick DD. Genetics and Molecular Pathogenesis of Human Hydrocephalus. Neurol India 2021; 69:S268-S274. [PMID: 35102976 DOI: 10.4103/0028-3886.332249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Hydrocephalus is a neurological disorder with an incidence of 80-125 per 100,000 live births in the United States. The molecular pathogenesis of this multidimensional disorder is complex and has both genetic and environmental influences. This review aims to discuss the genetic and molecular alterations described in human hydrocephalus, from well-characterized, heritable forms of hydrocephalus (e.g., X-linked hydrocephalus from L1CAM variants) to those affecting cilia motility and other complex pathologies such as neural tube defects and Dandy-Walker syndrome. Ventricular zone disruption is one key pattern among congenital and acquired forms of hydrocephalus, with abnormalities in cadherins, which mediate neuroepithelium/ependymal cell junctions and contribute to the pathogenesis and severity of the disease. Given the relationship between hydrocephalus pathogenesis and neurodevelopment, future research should elucidate the genetic and molecular mechanisms that regulate ventricular zone integrity and stem cell biology.
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Affiliation(s)
- Maria Garcia-Bonilla
- Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - James P McAllister
- Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - David D Limbrick
- Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
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47
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Loo CKC, Pearen MA, Ramm GA. The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes. Int J Mol Sci 2021; 22:ijms22189854. [PMID: 34576017 PMCID: PMC8468456 DOI: 10.3390/ijms22189854] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/03/2021] [Accepted: 09/09/2021] [Indexed: 12/18/2022] Open
Abstract
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
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Affiliation(s)
- Christine K. C. Loo
- South Eastern Area Laboratory Services, Department of Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Correspondence: ; Tel.: +61-2-93829015
| | - Michael A. Pearen
- Hepatic Fibrosis Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (M.A.P.); (G.A.R.)
| | - Grant A. Ramm
- Hepatic Fibrosis Group, Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; (M.A.P.); (G.A.R.)
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia
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48
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Mecklenburg N, Kowalczyk I, Witte F, Görne J, Laier A, Mamo TM, Gonschior H, Lehmann M, Richter M, Sporbert A, Purfürst B, Hübner N, Hammes A. Identification of disease-relevant modulators of the SHH pathway in the developing brain. Development 2021; 148:272000. [PMID: 34463328 DOI: 10.1242/dev.199307] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 07/19/2021] [Indexed: 12/13/2022]
Abstract
Pathogenic gene variants in humans that affect the sonic hedgehog (SHH) pathway lead to severe brain malformations with variable penetrance due to unknown modifier genes. To identify such modifiers, we established novel congenic mouse models. LRP2-deficient C57BL/6N mice suffer from heart outflow tract defects and holoprosencephaly caused by impaired SHH activity. These defects are fully rescued on a FVB/N background, indicating a strong influence of modifier genes. Applying comparative transcriptomics, we identified Pttg1 and Ulk4 as candidate modifiers upregulated in the rescue strain. Functional analyses showed that ULK4 and PTTG1, both microtubule-associated proteins, are positive regulators of SHH signaling, rendering the pathway more resilient to disturbances. In addition, we characterized ULK4 and PTTG1 as previously unidentified components of primary cilia in the neuroepithelium. The identification of genes that powerfully modulate the penetrance of genetic disturbances affecting the brain and heart is likely relevant to understanding the variability in human congenital disorders.
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Affiliation(s)
- Nora Mecklenburg
- Disorders of the Nervous System, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Izabela Kowalczyk
- Disorders of the Nervous System, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Franziska Witte
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Jessica Görne
- Disorders of the Nervous System, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Alena Laier
- Disorders of the Nervous System, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Tamrat M Mamo
- Disorders of the Nervous System, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Hannes Gonschior
- Cellular Imaging, Light Microscopy, Leibniz-Research Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany
| | - Martin Lehmann
- Cellular Imaging, Light Microscopy, Leibniz-Research Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany
| | - Matthias Richter
- Advanced Light Microscopy Technology Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Anje Sporbert
- Advanced Light Microscopy Technology Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Bettina Purfürst
- Electron microscopy technology platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
| | - Norbert Hübner
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Berlin, 10785 Berlin, Germany.,Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.,Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Annette Hammes
- Disorders of the Nervous System, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
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49
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de Castro VF, Mattos D, de Carvalho FM, Cavalcanti DP, Duenas-Roque MM, Llerena J, Cosentino VR, Honjo RS, Leite JCL, Sanseverino MT, de Souza MPA, Bernardi P, Bolognese AM, Santana da Silva LC, Barbero P, Correia PS, Bueno LSM, Savastano CP, Orioli IM. New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly. Mol Syndromol 2021; 12:219-233. [PMID: 34421500 DOI: 10.1159/000515044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 02/04/2021] [Indexed: 11/19/2022] Open
Abstract
Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH, SIX3, ZIC2, and TGIF1 genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHH variants and a third known SIX3 likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3 variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.
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Affiliation(s)
- Viviane Freitas de Castro
- ECLAMC at Departamento de Genética, UFRJ, Rio de Janeiro, Brazil.,Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil
| | - Daniel Mattos
- ECLAMC at Departamento de Genética, UFRJ, Rio de Janeiro, Brazil.,Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil
| | - Flavia Martinez de Carvalho
- Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil.,ECLAMC at Laboratorio Epidemiol. Malformações Congênitas, IOC/FIOCRUZ, Rio de Janeiro, Brazil
| | | | - Milagros M Duenas-Roque
- ECLAMC at Servicio de Genética, Hospital Nacional Edgardo Rebagliati Martins/EsSalud, Lima, Peru
| | - Juan Llerena
- Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil.,ECLAMC at Centro de Genética Médica, IFF/FIOCRUZ, Rio de Janeiro, Brazil
| | | | | | | | | | | | - Pricila Bernardi
- Núcleo de Genética Clínica, Departamento de Clínica Médica/UFSC, Florianópolis, Brazil
| | - Ana Maria Bolognese
- Departamento de Ortodontia, Faculdade de Odontologia/UFRJ, Rio de Janeiro, Brazil
| | - Luiz Carlos Santana da Silva
- Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil.,Laboratório de Erros Inatos de Metabolismo, Instituto de Ciências Biológicas/UFP, Belém, Brazil
| | - Pablo Barbero
- RENAC, Centro Nacional de Genética Médica Dr. Eduardo E. Castilla/MS, Buenos Aires, Argentina
| | | | | | | | - Iêda Maria Orioli
- ECLAMC at Departamento de Genética, UFRJ, Rio de Janeiro, Brazil.,Instituto Nacional de Genética Médica Populacional INAGEMP, Porto Alegre, Brazil
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Gao FJ, Klinedinst D, Fernandez FX, Cheng B, Savonenko A, Devenney B, Li Y, Wu D, Pomper MG, Reeves RH. Forebrain Shh overexpression improves cognitive function and locomotor hyperactivity in an aneuploid mouse model of Down syndrome and its euploid littermates. Acta Neuropathol Commun 2021; 9:137. [PMID: 34399854 PMCID: PMC8365939 DOI: 10.1186/s40478-021-01237-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/01/2021] [Indexed: 11/10/2022] Open
Abstract
Down syndrome (DS) is the leading genetic cause of intellectual disability and causes early-onset dementia and cerebellar hypoplasia. The prevalence of attention deficit hyperactivity disorder is elevated in children with DS. The aneuploid DS mouse model "Ts65Dn" shows prominent brain phenotypes, including learning and memory deficits, cerebellar hypoplasia, and locomotor hyperactivity. Previous studies indicate that impaired Sonic hedgehog (Shh) signaling contributes to neurological phenotypes associated with DS and neurodegenerative diseases. However, because of a lack of working inducible Shh knock-in mice, brain region-specific Shh overexpression and its effects on cognitive function have not been studied in vivo. Here, with Gli1-LacZ reporter mice, we demonstrated that Ts65Dn had reduced levels of Gli1, a sensitive readout of Shh signaling, in both hippocampus and cerebellum at postnatal day 6. Through site-specific transgenesis, we generated an inducible human Shh knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), simultaneously expressing dually-lipidated Shh-Np and Zsgreen1 marker in the presence of transactivator (tTA). Double transgenic mice "Camk2a-tTA;TRE-hShh" and "Pcp2-tTA;TRE-hShh" induced Shh overexpression and activated Shh signaling in a forebrain and cerebellum, respectively, specific manner from the perinatal period. Camk2a-tTA;TRE-hShh normalized locomotor hyperactivity and improved learning and memory in 3-month-old Ts65Dn, mitigated early-onset severe cognitive impairment in 7-month-old Ts65Dn, and enhanced spatial cognition in euploid mice. Camk2a-tTA;TRE-hShh cohort maintained until 600days old showed that chronic overexpression of Shh in forebrain from the perinatal period had no effect on longevity of euploid or Ts65Dn. Pcp2-tTA;TRE-hShh did not affect cognition but mitigated the phenotype of cerebellar hypoplasia in Ts65Dn. Our study provides the first in vivo evidence that Shh overexpression from the perinatal period protects DS brain integrity and enhances learning and memory in normal mice, indicating the broad therapeutic potential of Shh ligand for other neurological conditions. Moreover, the first inducible hShh site-specific knock-in mouse could be widely used for spatiotemporal Shh signaling regulation.
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Affiliation(s)
- Feng J Gao
- Department of Physiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
- Department of Genetic Medicine, John Hopkins University, Baltimore, MD, 21205, USA.
| | - Donna Klinedinst
- Department of Physiology, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Fabian-Xosé Fernandez
- Department of Psychology, University of Arizona, Tucson, AZ, USA
- Department of Neurology, University of Arizona, Tucson, AZ, USA
- BIO5 and McKnight Brain Research Institutes, Tucson, AZ, USA
| | - Bei Cheng
- Department of Radiology, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Alena Savonenko
- Department of Pathology and Neurology, John Hopkins University, Baltimore, MD, 21205, USA
| | - Benjamin Devenney
- Department of Physiology, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Yicong Li
- Department of Physiology, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Dan Wu
- Department of Biomedical Engineering, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Martin G Pomper
- Department of Radiology, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Roger H Reeves
- Department of Physiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
- Department of Genetic Medicine, John Hopkins University, Baltimore, MD, 21205, USA.
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