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Lan YZ, Wu Z, Chen WJ, Yu XN, Wu HT, Liu J. Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis. World J Clin Oncol 2025; 16:97163. [PMID: 39867730 PMCID: PMC11528897 DOI: 10.5306/wjco.v16.i1.97163] [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: 05/25/2024] [Revised: 09/20/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
The sine oculis homeobox homolog (SIX) family, a group of transcription factors characterized by a conserved DNA-binding homology domain, plays a critical role in orchestrating embryonic development and organogenesis across various organisms, including humans. Comprising six distinct members, from SIX1 to SIX6, each member contributes uniquely to the development and differentiation of diverse tissues and organs, underscoring the versatility of the SIX family. Dysregulation or mutations in SIX genes have been implicated in a spectrum of developmental disorders, as well as in tumor initiation and progression, highlighting their pivotal role in maintaining normal developmental trajectories and cellular functions. Efforts to target the transcriptional complex of the SIX gene family have emerged as a promising strategy to inhibit tumor development. While the development of inhibitors targeting this gene family is still in its early stages, the significant potential of such interventions holds promise for future therapeutic advances. Therefore, this review aimed to comprehensively explore the advancements in understanding the SIX family within gastrointestinal cancers, focusing on its critical role in normal organ development and its implications in gastrointestinal cancers, including gastric, pancreatic, colorectal cancer, and hepatocellular carcinomas. In conclusion, this review deepened the understanding of the functional roles of the SIX family and explored the potential of utilizing this gene family for the diagnosis, prognosis, and treatment of gastrointestinal cancers.
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Affiliation(s)
- Yang-Zheng Lan
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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2
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Swamynathan SK, Swamynathan S. Corneal epithelial development and homeostasis. Differentiation 2023; 132:4-14. [PMID: 36870804 PMCID: PMC10363238 DOI: 10.1016/j.diff.2023.02.002] [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: 10/26/2022] [Revised: 01/27/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023]
Abstract
The corneal epithelium (CE), the most anterior cellular structure of the eye, is a self-renewing stratified squamous tissue that protects the rest of the eye from external elements. Each cell in this exquisite three-dimensional structure needs to have proper polarity and positional awareness for the CE to serve as a transparent, refractive, and protective tissue. Recent studies have begun to elucidate the molecular and cellular events involved in the embryonic development, post-natal maturation, and homeostasis of the CE, and how they are regulated by a well-coordinated network of transcription factors. This review summarizes the status of related knowledge and aims to provide insight into the pathophysiology of disorders caused by disruption of CE development, and/or homeostasis.
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Affiliation(s)
| | - Sudha Swamynathan
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
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3
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Diacou R, Nandigrami P, Fiser A, Liu W, Ashery-Padan R, Cvekl A. Cell fate decisions, transcription factors and signaling during early retinal development. Prog Retin Eye Res 2022; 91:101093. [PMID: 35817658 PMCID: PMC9669153 DOI: 10.1016/j.preteyeres.2022.101093] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 12/30/2022]
Abstract
The development of the vertebrate eyes is a complex process starting from anterior-posterior and dorso-ventral patterning of the anterior neural tube, resulting in the formation of the eye field. Symmetrical separation of the eye field at the anterior neural plate is followed by two symmetrical evaginations to generate a pair of optic vesicles. Next, reciprocal invagination of the optic vesicles with surface ectoderm-derived lens placodes generates double-layered optic cups. The inner and outer layers of the optic cups develop into the neural retina and retinal pigment epithelium (RPE), respectively. In vitro produced retinal tissues, called retinal organoids, are formed from human pluripotent stem cells, mimicking major steps of retinal differentiation in vivo. This review article summarizes recent progress in our understanding of early eye development, focusing on the formation the eye field, optic vesicles, and early optic cups. Recent single-cell transcriptomic studies are integrated with classical in vivo genetic and functional studies to uncover a range of cellular mechanisms underlying early eye development. The functions of signal transduction pathways and lineage-specific DNA-binding transcription factors are dissected to explain cell-specific regulatory mechanisms underlying cell fate determination during early eye development. The functions of homeodomain (HD) transcription factors Otx2, Pax6, Lhx2, Six3 and Six6, which are required for early eye development, are discussed in detail. Comprehensive understanding of the mechanisms of early eye development provides insight into the molecular and cellular basis of developmental ocular anomalies, such as optic cup coloboma. Lastly, modeling human development and inherited retinal diseases using stem cell-derived retinal organoids generates opportunities to discover novel therapies for retinal diseases.
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Affiliation(s)
- Raven Diacou
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Prithviraj Nandigrami
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Andras Fiser
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Wei Liu
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Ruth Ashery-Padan
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Ales Cvekl
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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4
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Rzhanova LA, Kuznetsova AV, Aleksandrova MA. Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects. Russ J Dev Biol 2020. [DOI: 10.1134/s1062360420040062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Abstract
Impairment of the homeostatic and functional integrity of the retina and retinal pigment epithelium (RPE) is the main cause of some degenerative diseases of the human eye, which are accompanied by loss of eyesight. Despite the significant progress made over the past decades in the development of new methods for treatment for this pathology, there are still several complications when using surgical methods for correction of eyesight and so far insurmountable limitations in the applications of modern approaches, such as gene therapy and genetic engineering. One of the promising approaches to the treatment of degenerative diseases of the retina may be an approach based on the application of regenerative capacities of its endogenous cells with high plasticity, in particular, of RPE cells and Müller glia. Currently, vertebrate RPE cells are of great interest as a source of new photoreceptors and other neurons in the degrading retina in vivo. In this regard, the possibilities of their direct reprogramming by genetic, epigenetic, and chemical methods and their combination are being investigated. This review focuses on research in gene-directed reprogramming of vertebrate RPE cells into retinal neurons, with detailed analysis of the genes used as the main reprogramming factors, comparative analysis, and extrapolation of experimental data from animals to humans. Also, this review covers studies on the application of alternative approaches to gene-directed reprogramming, such as chemical-mediated reprogramming with the use of cocktails of therapeutic low-molecular-weight compounds and microRNAs. In general, the research results indicate the complexity of the process for direct reprogramming of human RPE cells into retinal neurons. However, taking into account the results of direct reprogramming of vertebrate cells and the accessibility of human RPE cells for various vectors that deliver a variety of molecules to cells, such as transcription factors, chimeric endonucleases, recombinant proteins, and low-weight molecular compounds, the most optimal combination of factors for the successful conversion of human RPE cells to retinal neurons can be suggested.
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Fiore L, Takata N, Acosta S, Ma W, Pandit T, Oxendine M, Oliver G. Optic vesicle morphogenesis requires primary cilia. Dev Biol 2020; 462:119-128. [PMID: 32169553 PMCID: PMC8167498 DOI: 10.1016/j.ydbio.2020.02.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 01/28/2020] [Accepted: 02/04/2020] [Indexed: 12/25/2022]
Abstract
Arl13b is a gene known to regulate ciliogenesis. Functional alterations in this gene's activity have been associated with Joubert syndrome. We found that in Arl13 null mouse embryos the orientation of the optic cup is inverted, such that the lens is abnormally surrounded by an inverted optic cup whose retina pigmented epithelium is oddly facing the surface ectoderm. Loss of Arl13b leads to the disruption of optic vesicle's patterning and expansion of ventral fates. We show that this phenotype is consequence of miss-regulation of Sonic hedgehog (Shh) signaling and demonstrate that the Arl13b-/- eye phenotype can be rescued by deletion of Gli2, a downstream effector of the Shh pathway. This work identified an unexpected role of primary cilia during the morphogenetic movements required for the formation of the eye.
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Affiliation(s)
- Luciano Fiore
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute (FCVRRI), Northwestern University, Chicago, IL, USA
| | - Nozomu Takata
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute (FCVRRI), Northwestern University, Chicago, IL, USA
| | - Sandra Acosta
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute (FCVRRI), Northwestern University, Chicago, IL, USA; Institute of Evolutive Biology, Pompeu Fabra University, Barcelona, Spain
| | - Wanshu Ma
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute (FCVRRI), Northwestern University, Chicago, IL, USA
| | - Tanushree Pandit
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Michael Oxendine
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute (FCVRRI), Northwestern University, Chicago, IL, USA
| | - Guillermo Oliver
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute (FCVRRI), Northwestern University, Chicago, IL, USA.
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6
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Liu Y, Wang J, Jin X, Xin Z, Wu X, Tong X, Tao Y, Wang D. A novel rat model of ocular hypertension by a single intracameral injection of cross-linked hyaluronic acid hydrogel (Healaflow ® ). Basic Clin Pharmacol Toxicol 2020; 127:361-370. [PMID: 32383327 DOI: 10.1111/bcpt.13430] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/26/2020] [Accepted: 05/03/2020] [Indexed: 12/28/2022]
Abstract
To create a novel animal model of ocular hypertension via the intracameral injection of Healaflow. Unilateral chronic ocular hypertension model of rats was created by the intracameral injection of 3 μL Healaflow. The IOP of subjects was monitored. Dynamic morphological changes were evaluated by fundus imaging, OCT and histological examination. Visual function changes were measured by electroretinography and flash visual-evoked potentials. 24 and 72 hours after injection, the retinal tissue was collected for transcriptome analysis. The expression levels of related genes and proteins were further evaluated by qRT-PCR and Western blotting. The IOP peaked within 1 day after a single intracameral injection of Healaflow and then decreased gradually within 4 weeks. Furthermore, the persistently degenerating retinal ganglion cells occurred within 4 weeks. The visual function of these rats was also impaired. The results of transcriptome analyses, qRT-PCR and Western blotting showed that the expression levels of B2m, Ikzf1 and Stat3 were up-regulated, while the expression levels of Six3 and Prss56 were down-regulated in the retinal tissues. Intracameral injection of Healaflow is an effective approach to induce glaucomatous neurodegeneration in rats. Six3 and Prss56 may be involved in the pathogenesis of progressive glaucomatous damage.
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Affiliation(s)
- Ying Liu
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of Ophthalmology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jichen Wang
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Xin Jin
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhiyuan Xin
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xing Wu
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xu Tong
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ye Tao
- Department of Ophthalmology, Henan Provincial People's Hospital, People's Hospital, Zhengzhou University, Zhengzhou, China
| | - Dajiang Wang
- Department of ophthalmology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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7
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Maire P, Dos Santos M, Madani R, Sakakibara I, Viaut C, Wurmser M. Myogenesis control by SIX transcriptional complexes. Semin Cell Dev Biol 2020; 104:51-64. [PMID: 32247726 DOI: 10.1016/j.semcdb.2020.03.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
SIX homeoproteins were first described in Drosophila, where they participate in the Pax-Six-Eya-Dach (PSED) network with eyeless, eyes absent and dachsund to drive synergistically eye development through genetic and biochemical interactions. The role of the PSED network and SIX proteins in muscle formation in vertebrates was subsequently identified. Evolutionary conserved interactions with EYA and DACH proteins underlie the activity of SIX transcriptional complexes (STC) both during embryogenesis and in adult myofibers. Six genes are expressed throughout muscle development, in embryonic and adult proliferating myogenic stem cells and in fetal and adult post-mitotic myofibers, where SIX proteins regulate the expression of various categories of genes. In vivo, SIX proteins control many steps of muscle development, acting through feedforward mechanisms: in the embryo for myogenic fate acquisition through the direct control of Myogenic Regulatory Factors; in adult myofibers for their contraction/relaxation and fatigability properties through the control of genes involved in metabolism, sarcomeric organization and calcium homeostasis. Furthermore, during development and in the adult, SIX homeoproteins participate in the genesis and the maintenance of myofibers diversity.
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Affiliation(s)
- Pascal Maire
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France.
| | | | - Rouba Madani
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France
| | - Iori Sakakibara
- Research Center for Advanced Science and Technology, The University of Tokyo, Japan
| | - Camille Viaut
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014, Paris, France
| | - Maud Wurmser
- Department of Integrative Medical Biology (IMB), Umeå universitet, Sweden
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8
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Ahmad I, Teotia P, Erickson H, Xia X. Recapitulating developmental mechanisms for retinal regeneration. Prog Retin Eye Res 2019; 76:100824. [PMID: 31843569 DOI: 10.1016/j.preteyeres.2019.100824] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/06/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022]
Abstract
Degeneration of specific retinal neurons in diseases like glaucoma, age-related macular degeneration, and retinitis pigmentosa is the leading cause of irreversible blindness. Currently, there is no therapy to modify the disease-associated degenerative changes. With the advancement in our knowledge about the mechanisms that regulate the development of the vertebrate retina, the approach to treat blinding diseases through regenerative medicine appears a near possibility. Recapitulation of developmental mechanisms is critical for reproducibly generating cells in either 2D or 3D culture of pluripotent stem cells for retinal repair and disease modeling. It is the key for unlocking the neurogenic potential of Müller glia in the adult retina for therapeutic regeneration. Here, we examine the current status and potential of the regenerative medicine approach for the retina in the backdrop of developmental mechanisms.
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Affiliation(s)
- Iqbal Ahmad
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
| | - Pooja Teotia
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Helen Erickson
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
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9
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Abstract
This chapter provides an overview of the early developmental origins of six ocular tissues: the cornea, lens, ciliary body, iris, neural retina, and retina pigment epithelium. Many of these tissue types are concurrently specified and undergo a complex set of morphogenetic movements that facilitate their structural interconnection. Within the context of vertebrate eye organogenesis, we also discuss the genetic hierarchies of transcription factors and signaling pathways that regulate growth, patterning, cell type specification and differentiation.
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Affiliation(s)
- Joel B Miesfeld
- Department of Cell Biology & Human Anatomy, University of California Davis School of Medicine, Davis, CA, United States
| | - Nadean L Brown
- Department of Cell Biology & Human Anatomy, University of California Davis School of Medicine, Davis, CA, United States.
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10
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The peripheral eye: A neurogenic area with potential to treat retinal pathologies? Prog Retin Eye Res 2018; 68:110-123. [PMID: 30201383 DOI: 10.1016/j.preteyeres.2018.09.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 08/31/2018] [Accepted: 09/03/2018] [Indexed: 12/14/2022]
Abstract
Numerous degenerative diseases affecting visual function, including glaucoma and retinitis pigmentosa, are produced by the loss of different types of retinal cells. Cell replacement therapy has emerged as a promising strategy for treating these and other retinal diseases. The retinal margin or ciliary body (CB) of mammals has been proposed as a potential source of cells to be used in degenerative conditions affecting the retina because it has been reported it might hold neurogenic potential beyond embryonic development. However, many aspects of the origin and biology of the CB are unknown and more recent experiments have challenged the capacity of CB cells to generate different types of retinal neurons. Here we review the most recent findings about the development of the marginal zone of the retina in different vertebrates and some of the mechanisms underlying the proliferative and neurogenic capacity of this fascinating region of the vertebrates eye. In addition, we performed experiments to isolate CB cells from the mouse retina, generated neurospheres and observed that they can be expanded with a proliferative ratio similar to neural stem cells. When induced to differentiate, cells derived from the CB neurospheres start to express early neural markers but, unlike embryonic stem cells, they are not able to fully differentiate in vitro or generate retinal organoids. Together with previous reports on the neurogenic capacity of CB cells, also reviewed here, our results contribute to the current knowledge about the potentiality of this peripheral region of the eye as a therapeutic source of functional retinal neurons in degenerative diseases.
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11
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Llonch S, Carido M, Ader M. Organoid technology for retinal repair. Dev Biol 2017; 433:132-143. [PMID: 29291970 DOI: 10.1016/j.ydbio.2017.09.028] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/05/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023]
Abstract
A major cause for vision impairment and blindness in industrialized countries is the loss of the light-sensing retinal tissue in the eye. Photoreceptor damage is one of the main characteristics found in retinal degeneration diseases, such as Retinitis Pigmentosa or age-related macular degeneration. The lack of effective therapies to stop photoreceptor loss together with the absence of significant intrinsic regeneration in the human retina converts such degenerative diseases into permanent conditions that are currently irreversible. Cell replacement by means of photoreceptor transplantation has been proposed as a potential approach to tackle cell loss in the retina. Since the first attempt of photoreceptor transplantation in humans, about twenty years ago, several research groups have focused in the development and improvement of technologies necessary to bring cell transplantation for retinal degeneration diseases to reality. Progress in recent years in the generation of human tissue derived from pluripotent stem cells (PSCs) has significantly improved our tools to study human development and disease in the dish. Particularly the availability of 3D culture systems for the generation of PSC-derived organoids, including the human retina, has dramatically increased access to human material for basic and medical research. In this review, we focus on important milestones towards the generation of transplantable photoreceptor precursors from PSC-derived retinal organoids and discuss recent pre-clinical transplantation studies using organoid-derived photoreceptors in context to related in vivo work using primary photoreceptors as donor material. Additionally, we summarize remaining challenges for developing photoreceptor transplantation towards clinical application.
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Affiliation(s)
- Sílvia Llonch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany
| | - Madalena Carido
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases Dresden (DZNE), Arnoldstraße 18, 01307 Dresden, Germany
| | - Marius Ader
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
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12
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Analysis of expression of transcription factors in early human retina. Int J Dev Neurosci 2017; 60:94-102. [PMID: 28377129 DOI: 10.1016/j.ijdevneu.2017.01.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 01/04/2017] [Accepted: 01/21/2017] [Indexed: 01/19/2023] Open
Abstract
The retina originates in the central nervous system. Due to its accessibility and simplicity, the retina has become an invaluable model for studying the basic mechanisms involved in development. To date, considerable knowledge regarding the interactions among genes that coordinate retinal development has been gained from extensive research in model animals. However, our understanding of retinal development in humans remains undeveloped. Here, we analyze the expression of transcription factors that are involved in the early development of the retina in human embryos at 6-12 weeks post-conception. Our work demonstrates that early developing neural retinas can be divided into two layers, the outer and inner neuroblast layers. Eye-field transcription factors and those related to the early development of the retina have distinct expression patterns in the two layers. Cell-type-specific transcription factors emerge at 8 weeks. These data provide clear and systemic structures for early retinal development in human.
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13
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Takata N, Sakakura E, Sasai Y. IGF-2/IGF-1R signaling has distinct effects on Sox1, Irx3, and Six3 expressions during ES cell derived-neuroectoderm development in vitro. In Vitro Cell Dev Biol Anim 2016; 52:607-15. [PMID: 26956358 DOI: 10.1007/s11626-016-0012-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 02/17/2016] [Indexed: 12/23/2022]
Abstract
Insulin-like growth factors (IGFs) are involved in growth and tissue development, including diseases such as type-2 diabetes and cancers. However, their roles in lineage specification, especially in early mammalian neural development, are poorly understood. Here, we analyzed the protein expression of IGF-2 in early mouse embryo, and it was preferentially detected in anterior mesodermal tissue, adjacent to the neural plate. We utilized a self-organizing neural tissue culture system and analyzed the direct effect of IGF-2 on the general neural marker Sox1. Interestingly, using recombinant IGF-2 and a chemical inhibitor of its receptor (IGF-1R), we found that the IGF-2/IGF-1R pathway positively regulated Sox1 expression in embryonic stem (ES) cell-derived neural tissue. Furthermore, to visualize the expression patterns of other neural markers, we used reporter ES cell lines and we found that the IGF-2/IGF-1R signaling upregulated the expression of the posterior neural marker Irx3. In contrast, the anterior neural marker Six3 was downregulated by IGF-2/IGF-1R signaling. Together, our results demonstrate that IGF-2/IGF-1R signaling has different effects on neural marker expression, which may influence the early regional identity of ES cell-derived neural tissues.
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Affiliation(s)
- Nozomu Takata
- Laboratory for In Vitro Histogenesis, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, 650-0047, Japan.
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 303 East Superior Street, Chicago, 60611, IL, USA.
| | - Eriko Sakakura
- Laboratory for In Vitro Histogenesis, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, 650-0047, Japan
| | - Yoshiki Sasai
- Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, 650-0047, Japan
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Beccari L, Marco-Ferreres R, Tabanera N, Manfredi A, Souren M, Wittbrodt B, Conte I, Wittbrodt J, Bovolenta P. A trans-Regulatory Code for the Forebrain Expression of Six3.2 in the Medaka Fish. J Biol Chem 2015; 290:26927-26942. [PMID: 26378230 PMCID: PMC4646366 DOI: 10.1074/jbc.m115.681254] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 09/11/2015] [Indexed: 12/16/2022] Open
Abstract
A well integrated and hierarchically organized gene regulatory network is responsible for the progressive specification of the forebrain. The transcription factor Six3 is one of the central components of this network. As such, Six3 regulates several components of the network, but its upstream regulators are still poorly characterized. Here we have systematically identified such regulators, taking advantage of the detailed functional characterization of the regulatory region of the medaka fish Six3.2 ortholog and of a time/cost-effective trans-regulatory screening, which complemented and overcame the limitations of in silico prediction approaches. The candidates resulting from this search were validated with dose-response luciferase assays and expression pattern criteria. Reconfirmed candidates with a matching expression pattern were also tested with chromatin immunoprecipitation and functional studies. Our results confirm the previously proposed direct regulation of Pax6 and further demonstrate that Msx2 and Pbx1 are bona fide direct regulators of early Six3.2 distribution in distinct domains of the medaka fish forebrain. They also point to other transcription factors, including Tcf3, as additional regulators of different spatial-temporal domains of Six3.2 expression. The activity of these regulators is discussed in the context of the gene regulatory network proposed for the specification of the forebrain.
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Affiliation(s)
- Leonardo Beccari
- Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, c/ Nicolas Cabrera 1, Madrid 28049, Spain,; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Nicolas Cabrera 1, Madrid 28049, Spain; Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda. Dr. Arce 37, Madrid, 28002, Spain,.
| | - Raquel Marco-Ferreres
- Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, c/ Nicolas Cabrera 1, Madrid 28049, Spain,; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Nicolas Cabrera 1, Madrid 28049, Spain; Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda. Dr. Arce 37, Madrid, 28002, Spain
| | - Noemi Tabanera
- Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, c/ Nicolas Cabrera 1, Madrid 28049, Spain,; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Nicolas Cabrera 1, Madrid 28049, Spain; Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda. Dr. Arce 37, Madrid, 28002, Spain
| | - Anna Manfredi
- Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda. Dr. Arce 37, Madrid, 28002, Spain
| | - Marcel Souren
- the Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
| | - Beate Wittbrodt
- the Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
| | - Ivan Conte
- Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda. Dr. Arce 37, Madrid, 28002, Spain,; the Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli, Naples, 80078, Italy
| | - Jochen Wittbrodt
- the Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 230, 69120 Heidelberg, Germany
| | - Paola Bovolenta
- Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, c/ Nicolas Cabrera 1, Madrid 28049, Spain,; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), c/ Nicolas Cabrera 1, Madrid 28049, Spain; Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda. Dr. Arce 37, Madrid, 28002, Spain,.
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15
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Yan RT, He L, Zhan W, Wang SZ. Induction of ectopic retina-like tissue by transgenic expression of neurogenin. PLoS One 2015; 10:e0116171. [PMID: 25635399 PMCID: PMC4312083 DOI: 10.1371/journal.pone.0116171] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 12/03/2014] [Indexed: 12/02/2022] Open
Abstract
Degeneration of retinal neurons is an underlying cause of several major types of blinding diseases, and effective therapies remain to be developed. The suppositive strategy of repopulating a degenerative retina with new cells generated onsite faces serious challenges, because the mammalian retina seems to lack the ability to regenerate itself or replace its lost neurons. We investigated the possibility of using a transcriptional factor with proneural activities to reprogram ocular tissue with regenerative capability to give rise to retinal cells. Transgenic mice were generated with DNA constructs that targeted the expression in the retinal pigment epithelium of proneural gene neurogenin1 from the promoter of Bestrophin1, or neurogenin3 from RPE65 promoter. Here we report the presence of ectopic retina-like tissue in some of the transgenic mice, young and aged. The ectopic retina-like tissue contained cells positive for photoreceptor proteins Crx, recoverin, red opsin, and rhodopsin, and cells positive for proteins that label other types of retinal neurons, including AP2α and Pax6 for amacrine cells, Otx2 for bipolar cells, and Brn3A for ganglion cells. The retina-like tissue often co-existed with darkly pigmented tissue positive for RPE proteins: cytokeratin 18, Otx2, and RPE65. The ectopic retina-like tissue was detected in the subretinal space, including two retinae co-existing in the same eye, and/or in the optic nerve or in the vicinity of the optic nerve head. On rare occasions, it was detected in the choroid and in the vicinity of the ciliary body. The presence of ectopic retina-like tissue in the transgenic mouse supports the possibility of inducing retinal regeneration in the mammalian eyes through gene-directed reprograming.
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Affiliation(s)
- Run-Tao Yan
- Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Li He
- Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Wenjie Zhan
- Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
| | - Shu-Zhen Wang
- Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America
- * E-mail:
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16
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Wu W, Ren Z, Li P, Yu D, Chen J, Huang R, Liu H. Six1: A critical transcription factor in tumorigenesis. Int J Cancer 2014; 136:1245-53. [DOI: 10.1002/ijc.28755] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 01/15/2014] [Accepted: 01/20/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Wangjun Wu
- Department of Animal Genetics; Breeding and Reproduction; College of Animal Science and Technology; Nanjing Agricultural University; Nanjing China
- Huaian Academy of Nanjing Agricultural University; Huaian Jiangsu China
| | - Zhuqing Ren
- Key Laboratory of Swine Genetics and Breeding; Ministry of Agriculture; Key Lab of Agriculture Animal Genetics; Breeding and Reproduction; Ministry of Education; College of Animal Science; Huazhong Agricultural University; Wuhan Hubei China
| | - Pinghua Li
- Department of Animal Genetics; Breeding and Reproduction; College of Animal Science and Technology; Nanjing Agricultural University; Nanjing China
| | - Debing Yu
- Department of Animal Genetics; Breeding and Reproduction; College of Animal Science and Technology; Nanjing Agricultural University; Nanjing China
| | - Jie Chen
- Department of Animal Genetics; Breeding and Reproduction; College of Animal Science and Technology; Nanjing Agricultural University; Nanjing China
| | - Ruihua Huang
- Department of Animal Genetics; Breeding and Reproduction; College of Animal Science and Technology; Nanjing Agricultural University; Nanjing China
| | - Honglin Liu
- Department of Animal Genetics; Breeding and Reproduction; College of Animal Science and Technology; Nanjing Agricultural University; Nanjing China
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17
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Setting appropriate boundaries: fate, patterning and competence at the neural plate border. Dev Biol 2013; 389:2-12. [PMID: 24321819 DOI: 10.1016/j.ydbio.2013.11.027] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 11/26/2013] [Accepted: 11/27/2013] [Indexed: 11/20/2022]
Abstract
The neural crest and craniofacial placodes are two distinct progenitor populations that arise at the border of the vertebrate neural plate. This border region develops through a series of inductive interactions that begins before gastrulation and progressively divide embryonic ectoderm into neural and non-neural regions, followed by the emergence of neural crest and placodal progenitors. In this review, we describe how a limited repertoire of inductive signals-principally FGFs, Wnts and BMPs-set up domains of transcription factors in the border region which establish these progenitor territories by both cross-inhibitory and cross-autoregulatory interactions. The gradual assembly of different cohorts of transcription factors that results from these interactions is one mechanism to provide the competence to respond to inductive signals in different ways, ultimately generating the neural crest and cranial placodes.
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18
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Iglesias AI, Springelkamp H, van der Linde H, Severijnen LA, Amin N, Oostra B, Kockx CEM, van den Hout MCGN, van IJcken WFJ, Hofman A, Uitterlinden AG, Verdijk RM, Klaver CCW, Willemsen R, van Duijn CM. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation–differentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet 2013; 23:1320-32. [DOI: 10.1093/hmg/ddt522] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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19
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Marlow H, Matus DQ, Martindale MQ. Ectopic activation of the canonical wnt signaling pathway affects ectodermal patterning along the primary axis during larval development in the anthozoan Nematostella vectensis. Dev Biol 2013; 380:324-34. [PMID: 23722001 PMCID: PMC4792810 DOI: 10.1016/j.ydbio.2013.05.022] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 04/22/2013] [Accepted: 05/20/2013] [Indexed: 10/26/2022]
Abstract
The primary axis of cnidarians runs from the oral pole to the apical tuft and defines the major body axis of both the planula larva and adult polyp. In the anthozoan cnidarian Nematostella vectensis, the primary oral-aboral (O-Ab) axis first develops during the early embryonic stage. Here, we present evidence that pharmaceutical activators of canonical wnt signaling affect molecular patterning along the primary axis of Nematostella. Although not overtly morphologically complex, molecular investigations in Nematostella reveal that the O-Ab axis is demarcated by the expression of differentially localized signaling molecules and transcription factors that may serve roles in establishing distinct ectodermal domains. We have further characterized the larval epithelium by determining the position of a nested set of molecular boundaries, utilizing several newly characterized as well as previously reported epithelial markers along the primary axis. We have assayed shifts in their position in control embryos and in embryos treated with the pharmacological agents alsterpaullone and azakenpaullone, Gsk3β inhibitors that act as canonical wnt agonists, and the Wnt antagonist iCRT14, following gastrulation. Agonist drug treatments result in an absence of aboral markers, a shift in the expression boundaries of oral markers toward the aboral pole, and changes in the position of differentially localized populations of neurons in a dose-dependent manner, while antagonist treatment had the opposite effect. These experiments are consistent with canonical wnt signaling playing a role in an orally localized wnt signaling center. These findings suggest that in Nematostella, wnt signaling mediates O-Ab ectodermal patterning across a surprisingly complex epithelium in planula stages following gastrulation in addition to previously described roles for the wnt signaling pathway in endomesoderm specification during gastrulation and overall animal-vegetal patterning at earlier stages of anthozoan development.
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20
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Ocular surface development and gene expression. J Ophthalmol 2013; 2013:103947. [PMID: 23533700 PMCID: PMC3595720 DOI: 10.1155/2013/103947] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 01/16/2013] [Indexed: 01/10/2023] Open
Abstract
The ocular surface-a continuous epithelial surface with regional specializations including the surface and glandular epithelia of the cornea, conjunctiva, and lacrimal and meibomian glands connected by the overlying tear film-plays a central role in vision. Molecular and cellular events involved in embryonic development, postnatal maturation, and maintenance of the ocular surface are precisely regulated at the level of gene expression by a well-coordinated network of transcription factors. A thorough appreciation of the biological characteristics of the ocular surface in terms of its gene expression profiles and their regulation provides us with a valuable insight into the pathophysiology of various blinding disorders that disrupt the normal development, maturation, and/or maintenance of the ocular surface. This paper summarizes the current status of our knowledge related to the ocular surface development and gene expression and the contribution of different transcription factors to this process.
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21
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Osakada F, Takahashi M. Stem Cells in the Developing and Adult Nervous System. Regen Med 2013. [DOI: 10.1007/978-94-007-5690-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Abstract
Three embryonic tissue sources-the neural ectoderm, the surface ectoderm, and the periocular mesenchyme-contribute to the formation of the mammalian eye. For this reason, the developing eye has presented an invaluable system for studying the interactions among cells and, more recently, genes, in specifying cell fate. This article describes how the eye primordium is specified in the anterior neural plate by four eye field transcription factors and how the optic vesicle becomes regionalized into three distinct tissue types. Specific attention is given to how cross talk between the optic vesicle and surface ectoderm contributes to lens and optic cup formation. This article also describes how signaling networks and cell movements set up axes in the optic cup and establish the multiple cell fates important for vision. How multipotent retinal progenitor cells give rise to the six neuronal and one glial cell type in the mature retina is also explained. Finally, the history and progress of cellular therapeutics for the treatment of degenerative eye disease is outlined. Throughout this article, special attention is given to how disruption of gene function causes ocular malformation in humans. Indeed, the accessibility of the eye has contributed much to our understanding of the basic processes involved in mammalian development.
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Affiliation(s)
- Whitney Heavner
- UNC Neuroscience Center, Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA
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23
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Zaghloul NA, Yan B, Moody SA. Step-wise specification of retinal stem cells during normal embryogenesis. Biol Cell 2012; 97:321-37. [PMID: 15836431 DOI: 10.1042/bc20040521] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The specification of embryonic cells to produce the retina begins at early embryonic stages as a multi-step process that gradually restricts fate potentials. First, a subset of embryonic cells becomes competent to form retina by their lack of expression of endo-mesoderm-specifying genes. From these cells, a more restricted subset is biased to form retina by virtue of their close proximity to sources of bone morphogenetic protein antagonists during neural induction. During gastrulation, the definitive RSCs (retinal stem cells) are specified as the eye field by interactions with underlying mesoderm and the expression of a network of retina-specifying genes. As the eye field is transformed into the optic vesicle and optic cup, a heterogeneous population of RPCs (retinal progenitor cells) forms to give rise to the different domains of the retina: the optic stalk, retinal pigmented epithelium and neural retina. Further diversity of RPCs appears to occur under the influences of cell-cell interactions, cytokines and combinations of regulatory genes, leading to the differentiation of a multitude of different retinal cell types. This review examines what is known about each sequential step in retinal specification during normal vertebrate development, and how that knowledge will be important to understand how RSCs might be manipulated for regenerative therapies to treat retinal diseases.
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Affiliation(s)
- Norann A Zaghloul
- Department of Anatomy and Cell Biology, The George Washington University, 2300 Eye Street, NW, Washington, DC 20037, USA
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24
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Eiraku M, Adachi T, Sasai Y. Relaxation-expansion model for self-driven retinal morphogenesis: a hypothesis from the perspective of biosystems dynamics at the multi-cellular level. Bioessays 2012; 34:17-25. [PMID: 22052700 PMCID: PMC3266490 DOI: 10.1002/bies.201100070] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The generation of complex organ structures such as the eye requires the intricate orchestration of multiple cellular interactions. In this paper, early retinal development is discussed with respect to the structure formation of the optic cup. Although recent studies have elucidated molecular mechanisms of retinal differentiation, little is known about how the unique shape of the optic cup is determined. A recent report has demonstrated that optic-cup morphogenesis spontaneously occurs in three-dimensional stem-cell culture without external forces, indicating a latent intrinsic order to generate the structure. Based on this self-organizing phenomenon, we introduce the "relaxation-expansion" model to mechanically interpret the tissue dynamics that enable the spontaneous invagination of the neural retina. This model involves three consecutive local rules (relaxation, apical constriction, and expansion), and its computer simulation recapitulates the optic-cup morphogenesis in silico.
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Affiliation(s)
- Mototsugu Eiraku
- Organogenesis and Neurogenesis Group, RIKEN Center for Developmental BiologyKobe, Japan
- Unit for Four-Dimensional Tissue Analysis, RIKEN Center for Developmental BiologyKobe, Japan
| | - Taiji Adachi
- Department of Biomechanics, Institute for Frontier Medical Sciences, Kyoto UniversityKyoto, Japan
- Computational Cell Biomechanics Team, VCAD System Research ProgramRIKEN, Wako, Japan
| | - Yoshiki Sasai
- Organogenesis and Neurogenesis Group, RIKEN Center for Developmental BiologyKobe, Japan
- Unit for Four-Dimensional Tissue Analysis, RIKEN Center for Developmental BiologyKobe, Japan
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25
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Posnien N, Koniszewski NDB, Hein HJ, Bucher G. Candidate gene screen in the red flour beetle Tribolium reveals six3 as ancient regulator of anterior median head and central complex development. PLoS Genet 2011; 7:e1002416. [PMID: 22216011 PMCID: PMC3245309 DOI: 10.1371/journal.pgen.1002416] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Accepted: 10/13/2011] [Indexed: 11/19/2022] Open
Abstract
Several highly conserved genes play a role in anterior neural plate patterning of vertebrates and in head and brain patterning of insects. However, head involution in Drosophila has impeded a systematic identification of genes required for insect head formation. Therefore, we use the red flour beetle Tribolium castaneum in order to comprehensively test the function of orthologs of vertebrate neural plate patterning genes for a function in insect head development. RNAi analysis reveals that most of these genes are indeed required for insect head capsule patterning, and we also identified several genes that had not been implicated in this process before. Furthermore, we show that Tc-six3/optix acts upstream of Tc-wingless, Tc-orthodenticle1, and Tc-eyeless to control anterior median development. Finally, we demonstrate that Tc-six3/optix is the first gene known to be required for the embryonic formation of the central complex, a midline-spanning brain part connected to the neuroendocrine pars intercerebralis. These functions are very likely conserved among bilaterians since vertebrate six3 is required for neuroendocrine and median brain development with certain mutations leading to holoprosencephaly.
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Affiliation(s)
- Nico Posnien
- Center for Molecular Physiology of the Brain (CMPB), Göttingen Center of Molecular Biology, Caspari-Haus, Georg-August-University Göttingen, Göttingen, Germany
- School of Life Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Nikolaus Dieter Bernhard Koniszewski
- Center for Molecular Physiology of the Brain (CMPB), Göttingen Center of Molecular Biology, Caspari-Haus, Georg-August-University Göttingen, Göttingen, Germany
| | | | - Gregor Bucher
- Center for Molecular Physiology of the Brain (CMPB), Göttingen Center of Molecular Biology, Caspari-Haus, Georg-August-University Göttingen, Göttingen, Germany
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26
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Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 2011; 472:51-6. [PMID: 21475194 DOI: 10.1038/nature09941] [Citation(s) in RCA: 1426] [Impact Index Per Article: 101.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Accepted: 02/17/2011] [Indexed: 12/20/2022]
Abstract
Balanced organogenesis requires the orchestration of multiple cellular interactions to create the collective cell behaviours that progressively shape developing tissues. It is currently unclear how individual, localized parts are able to coordinate with each other to develop a whole organ shape. Here we report the dynamic, autonomous formation of the optic cup (retinal primordium) structure from a three-dimensional culture of mouse embryonic stem cell aggregates. Embryonic-stem-cell-derived retinal epithelium spontaneously formed hemispherical epithelial vesicles that became patterned along their proximal-distal axis. Whereas the proximal portion differentiated into mechanically rigid pigment epithelium, the flexible distal portion progressively folded inward to form a shape reminiscent of the embryonic optic cup, exhibited interkinetic nuclear migration and generated stratified neural retinal tissue, as seen in vivo. We demonstrate that optic-cup morphogenesis in this simple cell culture depends on an intrinsic self-organizing program involving stepwise and domain-specific regulation of local epithelial properties.
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27
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Stem Cells in the Developing and Adult Nervous System. Regen Med 2011. [DOI: 10.1007/978-90-481-9075-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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28
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Liu W, Lagutin O, Swindell E, Jamrich M, Oliver G. Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate. J Clin Invest 2010; 120:3568-77. [PMID: 20890044 PMCID: PMC2947236 DOI: 10.1172/jci43219] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Accepted: 08/04/2010] [Indexed: 01/02/2023] Open
Abstract
Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.
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Affiliation(s)
- Wei Liu
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Oleg Lagutin
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Eric Swindell
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Milan Jamrich
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Guillermo Oliver
- Department of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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29
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Schlosser G. Making senses development of vertebrate cranial placodes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2010; 283:129-234. [PMID: 20801420 DOI: 10.1016/s1937-6448(10)83004-7] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Cranial placodes (which include the adenohypophyseal, olfactory, lens, otic, lateral line, profundal/trigeminal, and epibranchial placodes) give rise to many sense organs and ganglia of the vertebrate head. Recent evidence suggests that all cranial placodes may be developmentally related structures, which originate from a common panplacodal primordium at neural plate stages and use similar regulatory mechanisms to control developmental processes shared between different placodes such as neurogenesis and morphogenetic movements. After providing a brief overview of placodal diversity, the present review summarizes current evidence for the existence of a panplacodal primordium and discusses the central role of transcription factors Six1 and Eya1 in the regulation of processes shared between different placodes. Upstream signaling events and transcription factors involved in early embryonic induction and specification of the panplacodal primordium are discussed next. I then review how individual placodes arise from the panplacodal primordium and present a model of multistep placode induction. Finally, I briefly summarize recent advances concerning how placodal neurons and sensory cells are specified, and how morphogenesis of placodes (including delamination and migration of placode-derived cells and invagination) is controlled.
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Affiliation(s)
- Gerhard Schlosser
- Zoology, School of Natural Sciences & Martin Ryan Institute, National University of Ireland, Galway, Ireland
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30
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Domené S, Roessler E, El-Jaick KB, Snir M, Brown JL, Vélez JI, Bale S, Lacbawan F, Muenke M, Feldman B. Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum Mol Genet 2008; 17:3919-28. [PMID: 18791198 PMCID: PMC2733808 DOI: 10.1093/hmg/ddn294] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Accepted: 09/09/2008] [Indexed: 01/12/2023] Open
Abstract
Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain; however, the genetics of this heterogeneous and etiologically complex malformation is incompletely understood. Heterozygous mutations in SIX3, a transcription factor gene expressed in the anterior forebrain and eyes during early vertebrate development, have been frequently detected in human HPE cases. However, only a few mutations have been investigated with limited functional studies that would confirm a role in HPE pathogenesis. Here, we report the development of a set of robust and sensitive assays of human SIX3 function in zebrafish and apply these to the analysis of a total of 46 distinct mutations (19 previously published and 27 novel) located throughout the entire SIX3 gene. We can now confirm that 89% of these putative deleterious mutations are significant loss-of-function alleles. Since disease-associated single point mutations in the Groucho-binding eh1-like motif decreases the function in all assays, we can also confirm that this interaction is essential for human SIX3 co-repressor activity; we infer, in turn, that this function is important in HPE causation. We also unexpectedly detected truncated versions with partial function, yet missing a SIX3-encoded homeodomain. Our data indicate that SIX3 is a frequent target in the pathogenesis of HPE and demonstrate how this can inform the genetic counseling of families.
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Affiliation(s)
- Sabina Domené
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Erich Roessler
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Kenia B. El-Jaick
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Mirit Snir
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Jamie L. Brown
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Jorge I. Vélez
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | | | - Felicitas Lacbawan
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Maximilian Muenke
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
| | - Benjamin Feldman
- Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
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Mao CA, Wang SW, Pan P, Klein WH. Rewiring the retinal ganglion cell gene regulatory network: Neurod1 promotes retinal ganglion cell fate in the absence of Math5. Development 2008; 135:3379-88. [DOI: 10.1242/dev.024612] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Retinal progenitor cells (RPCs) express basic helix-loop-helix (bHLH)factors in a strikingly mosaic spatiotemporal pattern, which is thought to contribute to the establishment of individual retinal cell identity. Here, we ask whether this tightly regulated pattern is essential for the orderly differentiation of the early retinal cell types and whether different bHLH genes have distinct functions that are adapted for each RPC. To address these issues, we replaced one bHLH gene with another. Math5 is a bHLH gene that is essential for establishing retinal ganglion cell (RGC) fate. We analyzed the retinas of mice in which Math5 was replaced with Neurod1 or Math3, bHLH genes that are expressed in another RPC and are required to establish amacrine cell fate. In the absence of Math5, Math5Neurod1-KI was able to specify RGCs, activate RGC genes and restore the optic nerve, although not as effectively as Math5. By contrast, Math5Math3-KI was much less effective than Math5Neurod1-KI in replacing Math5. In addition, expression of Neurod1 and Math3 from the Math5Neurod1-KI/Math3-KIallele did not result in enhanced amacrine cell production. These results were unexpected because they indicated that bHLH genes, which are currently thought to have evolved highly specialized functions, are nonetheless able to adjust their functions by interpreting the local positional information that is programmed into the RPC lineages. We conclude that, although Neurod1 and Math3 have evolved specialized functions for establishing amacrine cell fate, they are nevertheless capable of alternative functions when expressed in foreign environments.
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Affiliation(s)
- Chai-An Mao
- Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Steven W. Wang
- Department of Ophthalmology and Visual Science, The University of Texas Houston Medical School, Houston, TX 77030, USA
| | - Ping Pan
- Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - William H. Klein
- Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
- Training Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
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Manuel M, Pratt T, Liu M, Jeffery G, Price DJ. Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance. BMC DEVELOPMENTAL BIOLOGY 2008; 8:59. [PMID: 18507827 PMCID: PMC2422841 DOI: 10.1186/1471-213x-8-59] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2007] [Accepted: 05/28/2008] [Indexed: 11/17/2022]
Abstract
Background The transcription factor Pax6 is expressed by many cell types in the developing eye. Eyes do not form in homozygous loss-of-function mouse mutants (Pax6Sey/Sey) and are abnormally small in Pax6Sey/+ mutants. Eyes are also abnormally small in PAX77 mice expressing multiple copies of human PAX6 in addition to endogenous Pax6; protein sequences are identical in the two species. The developmental events that lead to microphthalmia in PAX77 mice are not well-characterised, so it is not clear whether over- and under-expression of Pax6/PAX6 cause microphthalmia through similar mechanisms. Here, we examined the consequences of over-expression for the eye and its axonal connections. Results Eyes form in PAX77+/+ embryos but subsequently degenerate. At E12.5, we found no abnormalities in ocular morphology, retinal cell cycle parameters and the incidence of retinal cell death. From E14.5 on, we observed malformations of the optic disc. From E16.5 into postnatal life there is progressively more severe retinal dysplasia and microphthalmia. Analyses of patterns of gene expression indicated that PAX77+/+ retinae produce a normal range of cell types, including retinal ganglion cells (RGCs). At E14.5 and E16.5, quantitative RT-PCR with probes for a range of molecules associated with retinal development showed only one significant change: a slight reduction in levels of mRNA encoding the secreted morphogen Shh at E16.5. At E16.5, tract-tracing with carbocyanine dyes in PAX77+/+ embryos revealed errors in intraretinal navigation by RGC axons, a decrease in the number of RGC axons reaching the thalamus and an increase in the proportion of ipsilateral projections among those RGC axons that do reach the thalamus. A survey of embryos with different Pax6/PAX6 gene dosage (Pax6Sey/+, Pax6+/+, PAX77+ and PAX77+/+) showed that (1) the total number of RGC axons projected by the retina and (2) the proportions that are sorted into the ipsilateral and contralateral optic tracts at the optic chiasm vary differently with gene dosage. Increasing dosage increases the proportion projecting ipsilaterally regardless of the size of the total projection. Conclusion Pax6 overexpression does not obviously impair the initial formation of the eye and its major cell-types but prevents normal development of the retina from about E14.5, leading eventually to severe retinal degeneration in postnatal life. This sequence is different to that underlying microphthalmia in Pax6+/- heterozygotes, which is due primarily to defects in the initial stages of lens formation. Before the onset of severe retinal dysplasia, Pax6 overexpression causes defects of retinal axons, preventing their normal growth and navigation through the optic chiasm.
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Affiliation(s)
- Martine Manuel
- Genes and Development Group, Centres for Integrative Physiology and Neuroscience Research, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh EH8 9XD, UK.
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Appolloni I, Calzolari F, Corte G, Perris R, Malatesta P. Six3 controls the neural progenitor status in the murine CNS. Cereb Cortex 2008; 18:553-62. [PMID: 17576749 DOI: 10.1093/cercor/bhm092] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Six3, a homeodomain-containing transcriptional regulator belonging to the Six/so family, shows a defined spatiotemporal expression pattern in the developing murine telencephalon, suggesting that it may control the development of specific subsets of neural progenitors. We find that retrovirus-mediated misexpression of Six3 causes clonal expansion of isolated cortical progenitor cells by shortening their cell cycle and by prolonging their amplification period, while maintaining them in an immature precursor state. Our results show that the observed effects exerted by Six3 overexpression in mammalian brain depend strictly on the integrity of its DNA-binding domain, suggesting that Six3 action likely relies exclusively on its transcriptional activity. In vivo upregulation of Six3 expression in single progenitor cells of the embryonic telencephalon keeps them in an undifferentiated state. Our observations point to a role of Six3 in the control of the subtle equilibrium between proliferation and differentiation of defined precursor populations during mammalian neurogenesis.
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Affiliation(s)
- Irene Appolloni
- Istituto Nazionale per la Ricerca sul Cancro (IST), Largo Rosanna Benzi 10, 16132 Genoa, Italy
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Barembaum M, Bronner-Fraser M. Spalt4 mediates invagination and otic placode gene expression in cranial ectoderm. Development 2008; 134:3805-14. [PMID: 17933791 DOI: 10.1242/dev.02885] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Vertebrate placodes are regions of thickened head ectoderm that contribute to paired sensory organs and cranial ganglia. We demonstrate that the transcription factor Spalt4 (also known as Sall4) is broadly expressed in chick preplacodal epiblast and later resolves to otic, lens and olfactory placodes. Ectopic expression of Spalt4 by electroporation is sufficient to induce invagination of non-placodal head ectoderm and prevent neurogenic placodes from contributing to cranial ganglia. Conversely, loss of Spalt4 function in the otic placode results in abnormal otic vesicle development. Intriguingly, Spalt4 appears to initiate a placode program appropriate for the axial level but is not involved in later development of specific placode fates. Fgfs can regulate Spalt4, since implantation of Fgf2 beads into the area opaca induces its expression. The results suggest that Spalt4 is involved in early stages of placode development, initiating cranial ectodermal invagination and region-specific gene regulatory networks.
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Affiliation(s)
- Meyer Barembaum
- Division of Biology, 139-74, California Institute of Technology, Pasadena, CA 91125, USA
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35
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McCollum CW, Amin SR, Pauerstein P, Lane ME. A zebrafish LMO4 ortholog limits the size of the forebrain and eyes through negative regulation of six3b and rx3. Dev Biol 2007; 309:373-85. [PMID: 17692837 PMCID: PMC2100424 DOI: 10.1016/j.ydbio.2007.07.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2007] [Revised: 06/27/2007] [Accepted: 07/06/2007] [Indexed: 12/13/2022]
Abstract
The Six3 and Rx3 homeodomain proteins are essential for the specification and proliferation of forebrain and retinal precursor cells of the vertebrate brain, and the regulatory networks that control their expression are beginning to be elucidated. We identify the zebrafish lmo4b gene as a negative regulator of forebrain growth that acts via restriction of six3 and rx3 expression during early segmentation stages. Loss of lmo4b by morpholino knockdown results in enlargement of the presumptive telencephalon and optic vesicles and an expansion of the post-gastrula expression domains of six3 and rx3. Overexpression of lmo4b by mRNA injection causes complementary phenotypes, including a reduction in the amount of anterior neural tissue, especially in the telencephalic, optic and hypothalamic primordia, and a dosage-sensitive reduction in six3 and rx3 expression. We suggest that lmo4b activity is required at the neural boundary to restrict six3b expression, and later within the neural plate to for attenuation of rx3 expression independently of its effect on six3 transcription. We propose that lmo4b has an essential role in forebrain development as a modulator of six3 and rx3 expression, and thus indirectly influences neural cell fate commitment, cell proliferation and tissue growth in the anterior CNS.
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Affiliation(s)
| | - Shivas R. Amin
- Department of Biochemistry and Cell Biology, Rice University, Houston Texas 77005
| | - Philip Pauerstein
- Department of Biochemistry and Cell Biology, Rice University, Houston Texas 77005
| | - Mary Ellen Lane
- Department of Biochemistry and Cell Biology, Rice University, Houston Texas 77005
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36
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Geng X, Lavado A, Lagutin OV, Liu W, Oliver G. Expression of Six3 Opposite Strand (Six3OS) during mouse embryonic development. Gene Expr Patterns 2007; 7:252-7. [PMID: 17084678 PMCID: PMC1986792 DOI: 10.1016/j.modgep.2006.09.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2006] [Revised: 09/18/2006] [Accepted: 09/19/2006] [Indexed: 10/24/2022]
Abstract
Recently, sequence analyses have identified a large number of opposite strand transcripts in the vertebrate genome. Although the transcripts appear to be spliced and polyadenylated, many of them are predicted to represent noncoding RNAs. High levels of noncoding transcripts of the Six3 Opposite Strand (Six3OS) were recently identified in the embryonic and postnatal retina of the mouse. In this study, we expanded those initial expression analyses, elucidated in detail the developmental expression profile of mouse Six3OS in the brain and visual system, and compared it with that of Six3. Our results show that Six3OS expression overlaps extensively with that of Six3 and is not altered in Six3-null embryos.
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Affiliation(s)
- Xin Geng
- Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
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37
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Liu W, Lagutin OV, Mende M, Streit A, Oliver G. Six3 activation of Pax6 expression is essential for mammalian lens induction and specification. EMBO J 2006; 25:5383-95. [PMID: 17066077 PMCID: PMC1636621 DOI: 10.1038/sj.emboj.7601398] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2006] [Accepted: 09/26/2006] [Indexed: 01/31/2023] Open
Abstract
The homeobox gene Six3 regulates forebrain development. Here we show that Six3 is also crucial for lens formation. Conditional deletion of mouse Six3 in the presumptive lens ectoderm (PLE) disrupted lens formation. In the most severe cases, lens induction and specification were defective, and the lens placode and lens were absent. In Six3-mutant embryos, Pax6 was downregulated, and Sox2 was absent in the lens preplacodal ectoderm. Using ChIP, electrophoretic mobility shift assay, and luciferase reporter assays, we determined that Six3 activates Pax6 and Sox2 expression. Misexpression of mouse Six3 into chick embryos promoted the ectopic expansion of the ectodermal Pax6 expression domain. Our results position Six3 at the top of the regulatory pathway leading to lens formation. We conclude that Six3 directly activates Pax6 and probably also Sox2 in the PLE and regulates cell autonomously the earliest stages of mammalian lens induction.
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Affiliation(s)
- Wei Liu
- Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Oleg V Lagutin
- Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Michael Mende
- Department of Craniofacial Development, King's College London, London, UK
| | - Andrea Streit
- Department of Craniofacial Development, King's College London, London, UK
| | - Guillermo Oliver
- Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA
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38
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Donner AL, Episkopou V, Maas RL. Sox2 and Pou2f1 interact to control lens and olfactory placode development. Dev Biol 2006; 303:784-99. [PMID: 17140559 PMCID: PMC3276313 DOI: 10.1016/j.ydbio.2006.10.047] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2006] [Revised: 10/20/2006] [Accepted: 10/30/2006] [Indexed: 01/06/2023]
Abstract
Sox2, which encodes an SRY-like HMG box transcription factor, is critical for vertebrate development. Sox2 mediates its transcriptional effects through the formation of complexes with specific co-factors, many of which are unknown. In this report, we identify Oct-1, encoded by the Pou2f1 gene, as a co-factor for Sox2 in the context of mouse lens and nasal placode induction. Oct-1, Sox2, and Pax6 are co-expressed during lens and nasal placode induction and during subsequent developmental stages. Genetic combination of Sox2 and Pou2f1 mutant alleles results in impaired induction of the lens placode, an ocular phenotype that includes anophthalmia, and a complete failure of nasal placode induction. These ocular and nasal phenotypes closely resemble those observed in Pax6 null embryos. Moreover, we identify DNA-binding sites that support the cooperative formation of a complex between Sox2 and Oct-1 and mediate Sox2/Oct-1-dependent transactivation of the Pax6 lens ectoderm enhancer in vitro. We demonstrate that the same Sox- and Octamer-binding sites are essential for Pax6 enhancer activity in the lens placode and its derivatives in transgenic mouse embryos. Collectively, these results indicate that Pou2f1, Sox2 and Pax6 are interdependent components of a molecular pathway utilized in both lens and nasal placode induction.
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Affiliation(s)
- Amy L Donner
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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39
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Lord-Grignon J, Abdouh M, Bernier G. Identification of genes expressed in retinal progenitor/stem cell colonies isolated from the ocular ciliary body of adult mice. Gene Expr Patterns 2006; 6:992-9. [PMID: 16765103 DOI: 10.1016/j.modgep.2006.04.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2006] [Revised: 04/11/2006] [Accepted: 04/13/2006] [Indexed: 11/15/2022]
Abstract
Rare pigmented cells showing retinal stem cell characteristics have been identified in the ocular ciliary body (CB) of adult mammals. In vitro, these cells were reported to clonally proliferate and generate pigmented sphere colonies (PSC) containing multipotent retinal progenitor-like cells. Because these cells may have important clinical applications and because their embryonic origin is unclear, we have analyzed their local environment and gene expression profile. We found that transcription factors Pax6, Six3, and Rx, all involved in early eye morphogenesis, were expressed in the CB of adult mice. By sequencing a PSC cDNA library, we found that PSC expressed at high levels transcripts involved in the control of redox metabolism and cellular proliferation. PSC also expressed the retinal transcription factor Six6, which expression was not detected in the CB epithelium. By in situ hybridization screen, we found that Palmdelphin (Palm), Hmga2, and a novel transcript were expressed in the central nervous system of early embryos. Palm expression delineated the pigmented epithelium of the future CB and the developing myotome. Hmga2 was expressed in the ventricular zone of the telencephalon, the developing retinal ciliary margin and lens. Several genes expressed in PSC were also expressed in the nasal anlagen. Taken together, our study reveals that PSC isolated from the ocular CB express genes involved in the control of embryonic development, retinal identity, redox metabolism, and cellular proliferation.
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Affiliation(s)
- Julie Lord-Grignon
- Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, Canada H1T 2M4
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40
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Schlosser G. Induction and specification of cranial placodes. Dev Biol 2006; 294:303-51. [PMID: 16677629 DOI: 10.1016/j.ydbio.2006.03.009] [Citation(s) in RCA: 282] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 12/22/2005] [Accepted: 12/23/2005] [Indexed: 12/17/2022]
Abstract
Cranial placodes are specialized regions of the ectoderm, which give rise to various sensory ganglia and contribute to the pituitary gland and sensory organs of the vertebrate head. They include the adenohypophyseal, olfactory, lens, trigeminal, and profundal placodes, a series of epibranchial placodes, an otic placode, and a series of lateral line placodes. After a long period of neglect, recent years have seen a resurgence of interest in placode induction and specification. There is increasing evidence that all placodes despite their different developmental fates originate from a common panplacodal primordium around the neural plate. This common primordium is defined by the expression of transcription factors of the Six1/2, Six4/5, and Eya families, which later continue to be expressed in all placodes and appear to promote generic placodal properties such as proliferation, the capacity for morphogenetic movements, and neuronal differentiation. A large number of other transcription factors are expressed in subdomains of the panplacodal primordium and appear to contribute to the specification of particular subsets of placodes. This review first provides a brief overview of different cranial placodes and then synthesizes evidence for the common origin of all placodes from a panplacodal primordium. The role of various transcription factors for the development of the different placodes is addressed next, and it is discussed how individual placodes may be specified and compartmentalized within the panplacodal primordium. Finally, tissues and signals involved in placode induction are summarized with a special focus on induction of the panplacodal primordium itself (generic placode induction) and its relation to neural induction and neural crest induction. Integrating current data, new models of generic placode induction and of combinatorial placode specification are presented.
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Affiliation(s)
- Gerhard Schlosser
- Brain Research Institute, AG Roth, University of Bremen, FB2, 28334 Bremen, Germany.
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41
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Purcell P, Oliver G, Mardon G, Donner AL, Maas RL. Pax6-dependence of Six3, Eya1 and Dach1 expression during lens and nasal placode induction. Gene Expr Patterns 2005; 6:110-8. [PMID: 16024294 DOI: 10.1016/j.modgep.2005.04.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2005] [Revised: 04/15/2005] [Accepted: 04/18/2005] [Indexed: 11/17/2022]
Abstract
The Drosophila eyeless gene plays a central role in fly eye development and controls a subordinate regulatory network consisting of the so, eya and dac genes. All three genes have highly conserved mammalian homologs, suggesting possible conservation of this eye forming regulatory network. sine oculis (so) belongs to the so/Six gene family, and Six3 is prominently expressed in the developing mammalian eye. Eya1 and Dach1 are mammalian homologs of eya and dac, respectively, and although neither Eya1 nor Dach1 knockout mice express prenatal eye defects, possibilities exist for postnatal ocular phenotypes or for functional redundancy between related family members. To examine whether expression relationships analogous to those between ey, so, eya and dac exist in early mammalian oculogenesis, we investigated Pax6, Six3, Eya1 and Dach1 protein expression in murine lens and nasal placode development. Six3 expression in the pre-placode lens ectoderm is initially Pax6-independent, but subsequently both its expression and nuclear localization become Pax6-dependent. Six3, Dach1 and Eya1 nasal expression in pre-placode ectoderm are also initially Pax6-independent, but thereafter become Pax6-dependent. Pax6, Six3, Dach1 and Eya1 are all co-expressed in the developing ciliary marginal zone, a source of retinal stem cells in some vertebrates. An in vitro protein-protein interaction is detected between Six3 and Eya1. Collectively, these findings suggest that the Pax-Eya-Six-Dach network is at best only partly conserved during lens and nasal placode development. However, the findings do not rule out the possibility that such a regulatory network acts at later stages of oculogenesis.
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Affiliation(s)
- Patricia Purcell
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard, Medical School, New Research Building, Rm. 458H, 77, Avenue Louis Pasteur, Boston, MA 02115, USA
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Schlosser G. Evolutionary origins of vertebrate placodes: insights from developmental studies and from comparisons with other deuterostomes. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2005; 304:347-99. [PMID: 16003766 DOI: 10.1002/jez.b.21055] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ectodermal placodes comprise the adenohypophyseal, olfactory, lens, profundal, trigeminal, otic, lateral line, and epibranchial placodes. The first part of this review presents a brief overview of placode development. Placodes give rise to a variety of cell types and contribute to many sensory organs and ganglia of the vertebrate head. While different placodes differ with respect to location and derivative cell types, all appear to originate from a common panplacodal primordium, induced at the anterior neural plate border by a combination of mesodermal and neural signals and defined by the expression of Six1, Six4, and Eya genes. Evidence from mouse and zebrafish mutants suggests that these genes promote generic placodal properties such as cell proliferation, cell shape changes, and specification of neurons. The common developmental origin of placodes suggests that all placodes may have evolved in several steps from a common precursor. The second part of this review summarizes our current knowledge of placode evolution. Although placodes (like neural crest cells) have been proposed to be evolutionary novelties of vertebrates, recent studies in ascidians and amphioxus have proposed that some placodes originated earlier in the chordate lineage. However, while the origin of several cellular and molecular components of placodes (e.g., regionalized expression domains of transcription factors and some neuronal or neurosecretory cell types) clearly predates the origin of vertebrates, there is presently little evidence that these components are integrated into placodes in protochordates. A scenario is presented according to which all placodes evolved from an adenohypophyseal-olfactory protoplacode, which may have originated in the vertebrate ancestor from the anlage of a rostral neurosecretory organ (surviving as Hatschek's pit in present-day amphioxus).
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Abstract
The proteins termed TLE in humans, Grg in mice and Groucho in Drosophila constitute a family of transcriptional corepressors. In mammalians there are five different genes encoding an even larger number of proteins. Interactions between these TLE/Grg proteins and an array of transcription factors has been described. But is there any specificity? This review tries to make a case for a non-redundant function of individual TLE/Grg proteins. The specificity may be brought about by a tightly controlled temporo-spatial expression pattern, post-translational modifications, and subtle structural differences leading to distinct preferences for interacting transcription factors. A confirmation of this concept will ultimately need to come from genetic experiments.
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Affiliation(s)
- Malgorzata Gasperowicz
- Department of Internal Medicine, Division of Haematology and Oncology, University of Freiburg Medical Centre, 79106 Freiburg, Germany
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Litsiou A, Hanson S, Streit A. A balance of FGF, BMP and WNT signalling positions the future placode territory in the head. Development 2005; 132:4051-62. [PMID: 16093325 DOI: 10.1242/dev.01964] [Citation(s) in RCA: 211] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The sensory nervous system in the vertebrate head arises from two different cell populations: neural crest and placodal cells. By contrast, in the trunk it originates from neural crest only. How do placode precursors become restricted exclusively to the head and how do multipotent ectodermal cells make the decision to become placodes or neural crest? At neural plate stages,future placode cells are confined to a narrow band in the head ectoderm, the pre-placodal region (PPR). Here, we identify the head mesoderm as the source of PPR inducing signals, reinforced by factors from the neural plate. We show that several independent signals are needed: attenuation of BMP and WNT is required for PPR formation. Together with activation of the FGF pathway, BMP and WNT antagonists can induce the PPR in naïve ectoderm. We also show that WNT signalling plays a crucial role in restricting placode formation to the head. Finally, we demonstrate that the decision of multipotent cells to become placode or neural crest precursors is mediated by WNT proteins:activation of the WNT pathway promotes the generation of neural crest at the expense of placodes. This mechanism explains how the placode territory becomes confined to the head, and how neural crest and placode fates diversify.
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Affiliation(s)
- Anna Litsiou
- Department of Craniofacial Development, Guys Campus, Guys Tower, Floor 27, King's College London, London SE1 9RT, UK
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Aijaz S, Allen J, Tregidgo R, van Heyningen V, Hanson I, Clark BJ. Expression analysis of SIX3 and SIX6 in human tissues reveals differences in expression and a novel correlation between the expression of SIX3 and the genes encoding isocitrate dehyhrogenase and cadherin 18. Genomics 2005; 86:86-99. [PMID: 15953543 DOI: 10.1016/j.ygeno.2005.03.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2004] [Revised: 02/22/2005] [Accepted: 03/03/2005] [Indexed: 11/22/2022]
Abstract
SIX3 and SIX6 are transcription factors expressed during early stages of eye development. Limited expression data for SIX3 and SIX6 are available in the literature but, to date, there are no reports of the relative levels of expression of these genes throughout the human body and in adult tissues in particular. In this paper, we report extensive real-time quantitative PCR analyses of SIX3 and SIX6 expression in many different tissues of the adult human body, including ocular tissues, and a comparison of expression data with that of many other genes to identify similarity in expression. Using this powerful technique, we have detected a novel statistical correlation between the spatial distribution and the quantitative expression of SIX3 and 5 other transcripts including IDH1, the gene encoding the NADP(+)-dependent enzyme isocitrate dehydrogenase, and cadherin 18, type 2 (CDH14). Our data demonstrate that this novel technique can be used to generate hypotheses by comparison of gene expression profiles to identify possible interactions between genes or gene products.
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Affiliation(s)
- Saima Aijaz
- Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK
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Azuma N, Tadokoro K, Asaka A, Yamada M, Yamaguchi Y, Handa H, Matsushima S, Watanabe T, Kida Y, Ogura T, Torii M, Shimamura K, Nakafuku M. Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor. Hum Mol Genet 2005; 14:1059-68. [PMID: 15757974 DOI: 10.1093/hmg/ddi098] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The Pax6 gene plays an important role in eye morphogenesis throughout the animal kingdom. The Pax6 gene and its homologue could form ectopic eyes by targeted expression in Drosophila and Xenopus. Thus, this gene is a master gene for the eye morphogenesis at least in these animals. In the early development of the vertebrate eye, Pax6 is required for the instruction of multipotential progenitor cells of the neural retina (NR). Primitive retinal pigment epithelial (RPE) cells are able to switch their phenotype and differentiate into NR under exogenous intervention, including treatment with fibroblast growth factors (FGFs), and surgical removal of endogenous NR. However, the molecular basis of phenotypic switching is still controversial. Here, we show that Pax6 alone is sufficient to induce transdifferentiation of ectopic NR from RPE cells without addition of FGFs or surgical manipulation. Pax6-mediated transdifferentiation can be induced even at later stages of development. Both in vivo and in vitro studies show that the Pax6 lies downstream of FGF signaling, highlighting the central roles of Pax6 in NR transdifferentiation. Our results provide an evidence of retinogenic potential of nearly mature RPE and a cue for new therapeutic approaches to regenerate functional NR in patients with a visual loss.
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Affiliation(s)
- Noriyuki Azuma
- Department of Ophthalmology, National Center for Child Health and Development, Tokyo 157-8535, Japan.
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Roederer K, Cozy L, Anderson J, Kumar JP. Novel dominant-negative mutation within the six domain of the conserved eye specification gene sine oculis inhibits eye development in Drosophila. Dev Dyn 2005; 232:753-66. [PMID: 15704100 PMCID: PMC2737192 DOI: 10.1002/dvdy.20316] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The development of the compound eye of Drosophila is controlled, in part, by the concerted actions of several nuclear proteins that form an intricate regulatory system. One member of this network is sine oculis (so), the founding member of the Six gene family. Mutations within so affect the entire visual system, including the compound eye. The vertebrate homologs Six3 and Six6 also appear to play crucial roles in retinal formation. Mutations in Six3 inhibit retinal formation in chickens and fish, whereas those in Six6 are the underlying cause of bilateral anophthalmia in humans. Together, these phenotypes suggest a conserved role for the Six genes in eye development. In this report, we describe the effects of a dominant-negative mutation of sine oculis on the development of the compound eye of Drosophila. The mutation resides within the Six domain and may have implications for eye development and disease.
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Affiliation(s)
| | - Loralyn Cozy
- Department of Biology, Indiana University, Bloomington, Indiana
| | - Jason Anderson
- Department of Biology, Indiana University, Bloomington, Indiana
| | - Justin P. Kumar
- Department of Biology, Indiana University, Bloomington, Indiana
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48
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Abstract
Cranial placodes are a uniquely vertebrate characteristic; they form the paired sense organs of the eyes, ears and nose, in addition to the distal parts of some of the cranial sensory ganglia. These focal ectodermal thickenings have been studied from an embryological perspective in a diversity of organisms, revealing tissue interactions that are crucial for the morphological formation of the different placodes. In recent times, there has been a renewed interest in understanding the induction and differentiation of these deceptively simple ectodermal regions. This has led to a wealth of information on the molecular cues governing these processes. In particular, the integration of signals at the level of 'placode-specific' enhancers is beginning to provide a glimpse into the complexity of genetic networks that function within this embryonic cell population to generate key components of the peripheral nervous system.
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Affiliation(s)
- Sujata Bhattacharyya
- Division of Biology, MC 139-74, California Institute of Technology, Pasadena, California 91125, USA
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Streit A. Early development of the cranial sensory nervous system: from a common field to individual placodes. Dev Biol 2005; 276:1-15. [PMID: 15531360 DOI: 10.1016/j.ydbio.2004.08.037] [Citation(s) in RCA: 141] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2004] [Revised: 08/20/2004] [Accepted: 08/23/2004] [Indexed: 01/12/2023]
Abstract
Sensory placodes are unique columnar epithelia with neurogenic potential that develop in the vertebrate head ectoderm next to the neural tube. They contribute to the paired sensory organs and the cranial sensory ganglia generating a wide variety of cell types ranging from lens fibres to sensory receptor cells and neurons. Although progress has been made in recent years to identify the molecular players that mediate placode specification, induction and patterning, the processes that initiate placode development are not well understood. One hypothesis suggests that all placode precursors arise from a common territory, the pre-placodal region, which is then subdivided to generate placodes of specific character. This model implies that their induction begins through molecular and cellular mechanisms common to all placodes. Embryological and molecular evidence suggests that placode induction is a multi-step process and that the molecular networks establishing the pre-placodal domain as well as the acquisition of placodal identity are surprisingly similar to those used in Drosophila to specify sensory structures.
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Affiliation(s)
- Andrea Streit
- Department of Craniofacial Development, King's College London, Guy's Campus, London SE1 9RT, UK.
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50
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Abstract
Sensory placodes are unique domains of thickened ectoderm in the vertebrate head that form important parts of the cranial sensory nervous system, contributing to sense organs and cranial ganglia. They generate many different cell types, ranging from simple lens fibers to neurons and sensory cells. Although progress has been made to identify cell interactions and signaling pathways that induce placodes at precise positions along the neural tube, little is known about how their precursors are specified. Here, we review the evidence that placodes arise from a unique territory, the pre-placodal region, distinct from other ectodermal derivatives. We summarize the cellular and molecular mechanisms that confer pre-placode character and differentiate placode precursors from future neural and neural crest cells. We then examine the events that subdivide the pre-placodal region into individual placodes with distinct identity. Finally, we discuss the hypothesis that pre-placodal cells have acquired a state of "placode bias" that is necessary for their progression to mature placodes and how such bias may be established molecularly.
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Affiliation(s)
- Andrew P Bailey
- Department of Craniofacial Development Dental Institute at Guy's, King's College and St. Thomas' Hospitals, Guy's Campus London SE1 9RT, United Kingdom
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