Basic Research Open Access
Copyright ©The Author(s) 2004. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 15, 2004; 10(2): 264-267
Published online Jan 15, 2004. doi: 10.3748/wjg.v10.i2.264
Establishment of transgenic mice carrying gene encoding human zinc finger protein 191
Jian-Zhong Li, Hua Yang, Shui-Liang Wang, Ji-Liang Fu, Department of Medical Genetics, Second Military Medical University, Shanghai 200433, China
Zhu-Gang Wang, Ji-Liang Fu, Shanghai Nanfang Research Center for Biomodel Organism, Shanghai 201203, China
Long Yu, Genetics Institute, Fudan University, Shanghai 200433, China
Jian-Zhong Li, Xue-Lian Gong, Hao Feng, Bao-Yu Guo, Department of Biochemical Pharmacy, Second Military Medical University, Shanghai 200433, China
Xia Chen, Shanghai Research Center of Biotechnology, Chinese Academy of Sciences, Shanghai 200233, China
Author contributions: All authors contributed equally to the work.
Supported by the National Natural Science Foundation of China, No.39830360
Correspondence to: Professor Ji-Liang Fu, Department of Medical Genetics, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. jlfu@guomai.sh.cn
Telephone: +86-21-25070027 Fax: +86-21-25070027
Received: June 16, 2003
Revised: July 17, 2003
Accepted: July 24, 2003
Published online: January 15, 2004

Abstract

AIM: Human zinc finger protein 191 (ZNF191) was cloned and characterized as a Krüppel-like transcription factor, which might be relevant to many diseases such as liver cancer, neuropsychiatric and cardiovascular diseases. Although progress has been made recently, the biological function of ZNF191 remains largely unidentified. The aim of this study was to establish a ZNF 191 transgenic mouse model, which would promote the functional study of ZNF191.

METHODS: Transgene fragments were microinjected into fertilized eggs of mice. The manipulated embryos were transferred into the oviducts of pseudo-pregnant female mice. The offsprings were identified by PCR and Southern blot analysis. ZNF 191 gene expression was analyzed by RT-PCR. Transgenic founder mice were used to establish transgenic mouse lineages. The first generation (F1) and the second generation (F2) mice were identified by PCR analysis. Ten-week transgenic mice were used for pathological examination.

RESULTS: Four mice were identified as carrying copies of ZNF191 gene. The results of RT-PCR showed that ZNF 191 gene was expressed in the liver, testis and brain in one of the transgenic mouse lineages. Genetic analysis of transgenic mice demonstrated that ZNF 191 gene was integrated into the chromosome at a single site and could be transmitted stably. Pathological analysis showed that the expression of ZNF 191 did not cause obvious pathological changes in multiple tissues of transgenic mice.

CONCLUSION: ZNF 191 transgenic mouse model would facilitate the investigation of biological functions of ZNF191 in vivo.




INTRODUCTION

Transcriptional regulation is controlled through interactions between DNA and protein complex, the latter contains transcription factors with highly conserved protein motifs. The most well known motifs are helix-turn-helix, helix-loop-helix, and zinc finger. During cell differentiation and development, each of these domains is involved in the binding of transcription factors to their cognate DNA recognition sites, resulting in specific activation or repression of gene expression[1].

Zinc finger gene family belongs to one of the largest human gene families and plays an important role in the regulation of transcription. This large family may be divided into many subfamilies such as Cys2/His2 type, glucocorticoid receptor, ring finger, GATA-1 type, GAL4 type, and LIM family[2-4]. In the Cys2/His2 type of zinc finger genes, there is a highly conserved consensus sequence TGEKPYX (X representing any amino acid) between adjacent zinc finger motifs. The zinc finger proteins containing this specific structure are named Krüppel-like zinc finger proteins because the structure was first found in Drosophila Krüppel protein[1].

ZNF191 is a putative transcription factor belonging to Krüppel-like zinc finger gene family. It contains four Cys2/His2 zinc fingers in its C-terminus, and one SCAN box element (also known as LeR domain for leucine-rich) in its N-terminus[5-7]. Biochemical binding studies showed SCAN as a selective heterologous and homologous oligomerization domain[7,8]. Tissue mRNA analysis showed that ZNF191 gene was ubiquitously expressed[5,9]. ZNF191 can specifically bind to the TCAT repeats (HUMTH01) in the first intron of the human tyrosine hydroxylase (TH) gene. HUMTH01 may regulate transcription of TH gene, which encodes the rate-limiting enzyme in the synthesis of catecholamines[9-11]. The disturbances of catecholaminergic neurotransmission have been implicated in neuropsychiatric and cardiovascular diseases[12-17]. These studies suggested that ZNF191 might be relevant to these diseases. Analysis of amino acid sequence of ZNF191 showed 94% identity with the murine sequence of ZF-12[18]. Mouse ZF-12 gene likely represents the murine counterpart of human ZNF191. ZF-12 also contains four zinc finger motifs of the Cys2/His2 type and one SCAN box. ZF-12 mRNA is expressed during embryonic development and in different organs in adult[19]. ZF-12 may play an important role in cartilage differentiation and basic cellular processes[19].

To facilitate the functional studies of ZNF191, we established transgenic mice carrying ZNF191 gene. Four transgenic mice were identified by PCR and Southern blot, and used as founders to establish transgenic mouse lineages. The results of F1 identification with PCR showed that ZNF191 gene could be transmitted stably. RT-PCR analysis demonstrated that ZNF191 gene was expressed in multiple tissues of transgenic mice. Pathological analysis results demonstrated that over-expression of ZNF191 did not cause obvious pathological changes in multiple tissues of the transgenic mice.

MATERIALS AND METHODS
Plasmid

pcDNA3-ZNF191 containing full length ZNF191 cDNA under control of CMV promoter.

Animals

C57, CBA mice were maintained by Shanghai Nanfang Research Center for Biomodel Organism. Transgenic mice were raised and bred in the Laboratory Animal Centre of Second Military Medical University, Shanghai.

Generation of transgenic mice

The 6.5 kb linearized pcDNA3-ZNF191 was purified from agarose gel with QIAGEN gel extraction kit (Qiagen), adjusted to a final concentration of 2 μg/ml in TE buffer and used as DNA solution in microinjection. The first generation (F1) female hybrids of C57 and CBA mice were hormonally superovulated and mated with F1 male hybrids. The next morning fertilized one-cell eggs were collected from the oviduct. The eggs were microinjected with the DNA solution under a microscope. The injected fertilized eggs were transplanted into the oviduct of pseudo-pregnant F1 hybrids of C57 and CBA mice.

Identification of transgenic mice

Founder (G0) mice were identified by PCR and Southern blotting analysis. For PCR analysis, genomic DNA was extracted from tails, and amplified using pcDNA3-ZNF191 primers (P1: 5’-ATGCGGTGGGCTCTATG-3’; P2: 5’-CGGCTTCCATCCGAGTA-3’) which produced a 1 353 bp fragment from mice carrying the transgene. For Southern blotting analysis, genomic DNA was digested overnight with HindIII and subjected to electrophoresis in a 0.7% agarose gel and transferred to nylon membrane (Millipore Co., Ltd). Hybridization was performed under stringent conditions with a random-primed (α-32P)-labeled ZNF191 cDNA probe.

Expression of transgene

One of the transgenic mouse lineages was used to study the expression of transgene. Total RNA was isolated from tissues with TRIzol reagent (Invitrogen), according to the manufacturer’s instructions. After digestion of the RNA with DNase I (RNase free), first strand cDNA was synthesized by reverse transcription (Promega). RT-PCR reactions were performed using primers (P3:5’-GTACTAGTAGAAGACATGGT-3’, P4:5’-CGCACACAAAAGAACAAATCT-3’) for ZNF191 cDNA, which produced a 394 bp fragment. PCR reactions were performed 35 cycles at 95 °C for 45 s, at 55 °C for 1 min, and at 72 °C for 1 min. The PCR products were electrophoresed on 1.2% agarose gel.

Transmission of transgene

To study transmission of the transgene in mice, transgenic founder mice were mated with normal C57 mice to produce the first generation (F1) which was identified by PCR analysis using primers P1/P2. F1 mice of the same founder carrying the transgene were mated between brother and sister mice to produce the second generation (F2). F2 mice were also identified by PCR analysis.

Histological examination

Various organs were dissected from the 10 weeks old mice and fixed in 10% formalin. Sections were obtained from paraffin-embedded tissue samples, stained with H&E, and examined under a microscope and photographed. Pathological analysis was carried out in the Department of Pathology, Changhai Hospital of Second Military Medical University, Shanghai.

RESULTS
Establishment of ZNF191 transgenic mice

The transgene fragment containing full length ZNF191 cDNA was microinjected into the male pronuclei of 582 fertilized oocytes of F1 hybrids between C57 and CBA mice. The injected eggs were implanted into the oviducts of 27 pseudo-pregnant foster mothers, of which 15 mice became pregnant and gave birth to 81 offsprings. Four offsprings were identified to carry ZNF191 cDNA by PCR and Southern blotting analysis (Figures 1 and 2). The ratio of transgene integration was 4.9% by PCR and Southern blotting analysis.

Figure 1
Figure 1 PCR results in transgenic mice. M: DL-2000 Marker, 1: Negative control (wild type mouse), 2-5: Transgenic founder mice, 6: Positive control (pcDNA3-ZNF191).
Figure 2
Figure 2 Results of genomic DNA Southern blotting analysis in transgenic mice. 1: Negative control (wild type mouse), 2-5: Transgenic founder mice, 6: Positive control (pcDNA3-ZNF191).
ZNF191 transgene expression in multiple tissues of transgenic mice

The transgene was driven by CMV promoter. To study whether it could be expressed in multiple tissues of transgenic mice, we analysed the tissue expression profile of ZNF191 transgene by RT-PCR. The results (Figure 3) showed that ZNF191 transgene was expressed in the liver, testis and brain.

Figure 3
Figure 3 RT-PCR results in transgene expression. M: DL-2000 Marker, 1-3: Transgenic mice tissues, 4-5: Negative control (non-reverse transcripted RNA), 6:C57 mouse liver, 7: Positive control (pcDNA3-ZNF191).
Genetics of transgenic mice

To establish transgenic mouse lineages, the founder mice were mated to C57 mice to produce F1 mice. Among the 43 mice of first generation, 19 were identified as carrying ZNF191 cDNA transgene by PCR analysis. The ratio of transgene transmission was 44.2%. F1 mice from the same founder were mated with each other to produce F2 mice. Sixty-one out of 86 F2 mice were ZNF191 transgenic mice, with a transgene transmission ratio of 71%. These results showed that the inheritance of ZNF191 transgene was in accordance with Mendel’s laws, and the transgene was integrated into the chromosome at a single site and could be transmitted stably.

Pathological analysis of tissues

Pathological analysis was carried out to see whether the expression of ZNF191 transgene would cause any pathological changes in tissues of the transgenic mice. The results (Figure 4) showed there were no obvious pathological changes in the tissues examined. Therefore, so far as the tissues examined, the expression of exogenous ZNF191 did not cause any pathological consequences in the transgenic mice.

Figure 4
Figure 4 Morphology of tissues of transgenic mouse. A: Liver, B: Testis, C: Marrow, D: Brain, E: Kidney, F: Spleen.
DISCUSSION

Cys2/His2 type zinc finger gene family is one of the largest gene families, and each member has repeated zinc finger motifs containing a finger-like structure, in which two cysteines and two histidines could covalently bind to one zinc ion[20]. It is estimated that in this huge family, about one third of the members are Krüppel-like genes as characterized by the presence of highly conserved connecting sequences “TGEKPYX” between adjacent zinc finger motifs. Substantial evidences indicate that Krüppel proteins are important players in many physiological processes as transcriptional regulators. Krüppel-like zinc finger genes are key transcriptional repressors in the development of Drosophila. In mammalian animals and human, these genes have been found involved in embryo development and carcinogenesis. For example, KLF6 was reported as a tumor suppressor gene in prostate cancer[21-23]. Gut-enriched Krüppel-like factor (GKLF) was expressed abundantly in epithelial cells of gastrointestinal tract, and deregulation of GKLF was linked to several types of cancer[24-27].

ZNF191 gene is a novel member of the Krüppel-like zinc finger gene family. It was previously cloned from bone marrow and promyelocytic leukemia cell line NB4 using homologous PCR amplification with primers based on conserved sequences of the Krüppel-like family of transcription factors[5]. This first identification suggested that ZNF191 played a role in hematopoiesis. ZNF191 has been found to contain a SCAN domain mediating selective protein oligomerization[6-8]. ZNF191 specifically binds to HUMTH01 in vitro. The microsatellite HUMTH01, located at the first intron of tyrosine hydroxylase (TH) gene, is characterized by a TCAT repeated motif and has been used in genetic studies of neuropsychiatric and cardiovascular diseases, in which disturbances of catecholaminergic neurotransmission were implicated[10-17]. Allelic variations of HUMTH01 had a quantitative silencing effect on TH gene expression in vitro, and correlated with quantitative and qualitative changes in the binding by ZNF191[9]. Since TCAT repeated sequence is widespread throughout the genome, this phenomenon might be relevant to the quantitative expression of several genes implicated in complex genetic traits, both normal and pathological[28-31]. These studies suggested that ZNF191 might be relevant to neuropsychiatric and cardiovascular diseases. It is vital to have a transgenic or knock-out animal model for the study of the biological role of ZNF191. So far, the attempt to produce ZNF191 transgenic and knock-out mice has not been reported. To our knowledge, we have generated the first transgenic mice carrying ZNF191 transgene and ZF-12+/- mice (to be reported in an other paper).

In in vivo situation, ZNF191 transcript was found in various organs[5,9]. Moreover, ZNF191 expression was significantly up-regulated in liver cancer (personal communication), suggesting that ZNF191 might be relevant to hepatocellular carcinogenesis. In this study, ZNF191 transgene was expressed in multiple tissues, which are capable of expressing endogenous ZF-12 in vivo. Therefore, the ZNF191 transgenic mouse we generated would be an invaluable animal model not only for the investigation of ZNF191 functions in hepatic tissues, but also in other tissues, which may ultimately reveal the undefined biological functions of ZNF191.

Given that ZNF191 has important biological functions and is relevant to many diseases, it is somewhat unexpected that no pathological changes occurred in the ten-week transgenic mice with ZNF191 over-expression. It is possible that overexpression of exogenous ZNF191 may trigger a negative feedback response to the expression of endogenous ZF-12. It remains to be determined whether the expression of endogenous ZF-12 would change in cells overexpressing exogenous ZNF191. On the other hand, liver cancer, neuropsychiatric and cardiovascular diseases involve many factors and usually have a long incubation time before any pathological phenotypes can be observed. So, it is necessary to continue the investigation into possible pathological changes in a long term follow-up.

In conclusion, we reported here the successful generation of a transgenic mouse model expressing ZNF191 gene. Future studies should focus on the physiological and pathological changes in this mouse model using powerful analytic methods such as microarray comparisons of gene expression profiles among normal, transgenic, ZF-12+/- and ZF-12-/- mice.

Footnotes

Edited by Zhu LH and Wang XL

References
1.  Klug A, Schwabe JW. Protein motifs 5. Zinc fingers. FASEB J. 1995;9:597-604.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Borden KL, Freemont PS. The RING finger domain: a recent example of a sequence-structure family. Curr Opin Struct Biol. 1996;6:395-401.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 372]  [Cited by in F6Publishing: 361]  [Article Influence: 12.9]  [Reference Citation Analysis (0)]
3.  Hammarström A, Berndt KD, Sillard R, Adermann K, Otting G. Solution structure of a naturally-occurring zinc-peptide complex demonstrates that the N-terminal zinc-binding module of the Lasp-1 LIM domain is an independent folding unit. Biochemistry. 1996;35:12723-12732.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 47]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
4.  Barlow PN, Luisi B, Milner A, Elliott M, Everett R. Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy. A new structural class of zinc-finger. J Mol Biol. 1994;237:201-211.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 205]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
5.  Han ZG, Zhang QH, Ye M, Kan LX, Gu BW, He KL, Shi SL, Zhou J, Fu G, Mao M. Molecular cloning of six novel Krüppel-like zinc finger genes from hematopoietic cells and identification of a novel transregulatory domain KRNB. J Biol Chem. 1999;274:35741-35748.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 56]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
6.  Collins T, Stone JR, Williams AJ. All in the family: the BTB/POZ, KRAB, and SCAN domains. Mol Cell Biol. 2001;21:3609-3615.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 269]  [Cited by in F6Publishing: 277]  [Article Influence: 12.0]  [Reference Citation Analysis (0)]
7.  Stone JR, Maki JL, Blacklow SC, Collins T. The SCAN domain of ZNF174 is a dimer. J Biol Chem. 2002;277:5448-5452.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 28]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
8.  Schumacher C, Wang H, Honer C, Ding W, Koehn J, Lawrence Q, Coulis CM, Wang LL, Ballinger D, Bowen BR. The SCAN domain mediates selective oligomerization. J Biol Chem. 2000;275:17173-17179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 68]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
9.  Albanèse V, Biguet NF, Kiefer H, Bayard E, Mallet J, Meloni R. Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite. Hum Mol Genet. 2001;10:1785-1792.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 96]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
10.  Meloni R, Albanèse V, Ravassard P, Treilhou F, Mallet J. A tetranucleotide polymorphic microsatellite, located in the first intron of the tyrosine hydroxylase gene, acts as a transcription regulatory element in vitro. Hum Mol Genet. 1998;7:423-428.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 105]  [Cited by in F6Publishing: 111]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
11.  Mallet J. The TiPS/TINS lecture. Catecholamines: from gene regulation to neuropsychiatric disorders. Trends Pharmacol Sci. 1996;17:129-135.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 12]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
12.  Sharma P, Hingorani A, Jia H, Ashby M, Hopper R, Clayton D, Brown MJ. Positive association of tyrosine hydroxylase microsatellite marker to essential hypertension. Hypertension. 1998;32:676-682.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 54]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
13.  Meloni R, Leboyer M, Bellivier F, Barbe B, Samolyk D, Allilaire JF, Mallet J. Association of manic-depressive illness with tyrosine hydroxylase microsatellite marker. Lancet. 1995;345:932.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 60]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
14.  Pérez de Castro I, Santos J, Torres P, Visedo G, Saiz-Ruiz J, Llinares C, Fernández-Piqueras J. A weak association between TH and DRD2 genes and bipolar affective disorder in a Spanish sample. J Med Genet. 1995;32:131-134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 43]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
15.  Serretti A, Macciardi F, Verga M, Cusin C, Pedrini S, Smeraldi E. Tyrosine hydroxylase gene associated with depressive symptomatology in mood disorder. Am J Med Genet. 1998;81:127-130.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
16.  Meloni R, Laurent C, Campion D, Ben Hadjali B, Thibaut F, Dollfus S, Petit M, Samolyk D, Martinez M, Poirier MF. A rare allele of a microsatellite located in the tyrosine hydroxylase gene found in schizophrenic patients. C R Acad Sci III. 1995;318:803-809.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Wei J, Ramchand CN, Hemmings GP. Possible association of catecholamine turnover with the polymorphic (TCAT)n repeat in the first intron of the human tyrosine hydroxylase gene. Life Sci. 1997;61:1341-1347.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 29]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
18.  Li JZ, Chen X, Wang SL, Sun X, Zhang YZ, Yu L, Fu JL. [Cloning, genomic organization and promoter activity of the mouse zinc finger protein gene ZF-12]. Yi Chuan Xue Bao. 2003;30:311-316.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Prost JF, Nègre D, Cornet-Javaux F, Cortay JC, Cozzone AJ, Herbage D, Mallein-Gerin F. Isolation, cloning, and expression of a new murine zinc finger encoding gene. Biochim Biophys Acta. 1999;1447:278-283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 11]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
20.  Jacobs GH. Determination of the base recognition positions of zinc fingers from sequence analysis. EMBO J. 1992;11:4507-4517.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Chen C, Hyytinen ER, Sun X, Helin HJ, Koivisto PA, Frierson HF, Vessella RL, Dong JT. Deletion, mutation, and loss of expression of KLF6 in human prostate cancer. Am J Pathol. 2003;162:1349-1354.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 116]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
22.  Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM. KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science. 2001;294:2563-2566.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 334]  [Cited by in F6Publishing: 340]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
23.  Narla G, Friedman SL, Martignetti JA. Krüppel cripples prostate cancer: KLF6 progress and prospects. Am J Pathol. 2003;162:1047-1052.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 27]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
24.  Stone CD, Chen ZY, Tseng CC. Gut-enriched Krüppel-like factor regulates colonic cell growth through APC/beta-catenin pathway. FEBS Lett. 2002;530:147-152.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 37]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
25.  Wang N, Liu ZH, Ding F, Wang XQ, Zhou CN, Wu M. Down-regulation of gut-enriched Kruppel-like factor expression in esophageal cancer. World J Gastroenterol. 2002;8:966-970.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Chen ZY, Shie JL, Tseng CC. Gut-enriched Kruppel-like factor represses ornithine decarboxylase gene expression and functions as checkpoint regulator in colonic cancer cells. J Biol Chem. 2002;277:46831-46839.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 57]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
27.  Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development. 2002;129:2619-2628.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Meloni R, Biguet NF, Mallet J. Post-genomic era and gene discovery for psychiatric diseases: there is a new art of the trade The example of the HUMTH01 microsatellite in the Tyrosine Hydroxylase gene. Mol Neurobiol. 2002;26:389-403.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
29.  Schadt EE, Monks SA, Drake TA, Lusis AJ, Che N, Colinayo V, Ruff TG, Milligan SB, Lamb JR, Cavet G. Genetics of gene expression surveyed in maize, mouse and man. Nature. 2003;422:297-302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1148]  [Cited by in F6Publishing: 1038]  [Article Influence: 49.4]  [Reference Citation Analysis (0)]
30.  Mackay TF. The genetic architecture of quantitative traits. Annu Rev Genet. 2001;35:303-339.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 802]  [Cited by in F6Publishing: 657]  [Article Influence: 29.9]  [Reference Citation Analysis (0)]
31.  Reif A, Lesch KP. Toward a molecular architecture of personality. Behav Brain Res. 2003;139:1-20.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 148]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]