GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary
Background & Aims: The embryonic small intestinal epithelium is highly proliferative, and although much is known about mechanisms regulating proliferation in the adult intestine, the mechanisms controlling epithelial cell proliferation in the developing intestine are less clear. GATA4, a transcr...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X15001939 |
| _version_ | 1818624371796738048 |
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| author | Bridget M. Kohlnhofer Cayla A. Thompson Emily M. Walker Michele A. Battle |
| author_facet | Bridget M. Kohlnhofer Cayla A. Thompson Emily M. Walker Michele A. Battle |
| author_sort | Bridget M. Kohlnhofer |
| collection | DOAJ |
| description | Background & Aims: The embryonic small intestinal epithelium is highly proliferative, and although much is known about mechanisms regulating proliferation in the adult intestine, the mechanisms controlling epithelial cell proliferation in the developing intestine are less clear. GATA4, a transcription factor that regulates proliferation in other developing tissues, is first expressed early in the developing gut in midgut endoderm. GATA4 function within midgut endoderm and the early intestinal epithelium is unknown. Methods: By using Sonic Hedgehog Cre to eliminate GATA4 in the midgut endoderm of mouse embryos, we determined the impact of loss of GATA4 on intestinal development, including epithelial cell proliferation, between embryonic day (E)9.5 and E18.5. Results: We found that intestinal length and width were decreased in GATA4 mutants compared with controls. GATA4-deficient intestinal epithelium contained fewer cells, and epithelial girth was decreased. We further observed a decreased proportion of proliferating epithelial cells at E10.5 and E11.5 in GATA4 mutants. We showed that GATA4 binds to chromatin containing GATA4 consensus binding sites within cyclin D2 (Ccnd2), cyclin-dependent kinase 6 (Cdk6), and frizzled 5 (Fzd5). Moreover, Ccnd2, Cdk6, and Fzd5 transcripts were reduced at E11.5 in GATA4 mutant tissue. Villus morphogenesis was delayed, and villus structure was abnormal in GATA4 mutant intestine. Conclusions: Our data identify GATA4 as an essential regulator of early intestinal epithelial cell proliferation. We propose that GATA4 controls proliferation in part by directly regulating transcription of cell-cycle mediators. Our data further suggest that GATA4 affects proliferation through transcriptional regulation of Fzd5, perhaps by influencing the response of the epithelium to WNT signaling. Keywords: Transcriptional Regulation, WNT Signaling, Villus Morphogenesis |
| first_indexed | 2024-12-16T18:55:54Z |
| format | Article |
| id | doaj.art-b3a25fb1b5f140359dbdd8659109b238 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-16T18:55:54Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-b3a25fb1b5f140359dbdd8659109b2382022-12-21T22:20:32ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2016-03-0122189209GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummaryBridget M. Kohlnhofer0Cayla A. Thompson1Emily M. Walker2Michele A. Battle3Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WisconsinDepartment of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WisconsinDepartment of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WisconsinCorrespondence Address correspondence to: Michele A. Battle, PhD, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226. fax: (414) 955-6517.; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WisconsinBackground & Aims: The embryonic small intestinal epithelium is highly proliferative, and although much is known about mechanisms regulating proliferation in the adult intestine, the mechanisms controlling epithelial cell proliferation in the developing intestine are less clear. GATA4, a transcription factor that regulates proliferation in other developing tissues, is first expressed early in the developing gut in midgut endoderm. GATA4 function within midgut endoderm and the early intestinal epithelium is unknown. Methods: By using Sonic Hedgehog Cre to eliminate GATA4 in the midgut endoderm of mouse embryos, we determined the impact of loss of GATA4 on intestinal development, including epithelial cell proliferation, between embryonic day (E)9.5 and E18.5. Results: We found that intestinal length and width were decreased in GATA4 mutants compared with controls. GATA4-deficient intestinal epithelium contained fewer cells, and epithelial girth was decreased. We further observed a decreased proportion of proliferating epithelial cells at E10.5 and E11.5 in GATA4 mutants. We showed that GATA4 binds to chromatin containing GATA4 consensus binding sites within cyclin D2 (Ccnd2), cyclin-dependent kinase 6 (Cdk6), and frizzled 5 (Fzd5). Moreover, Ccnd2, Cdk6, and Fzd5 transcripts were reduced at E11.5 in GATA4 mutant tissue. Villus morphogenesis was delayed, and villus structure was abnormal in GATA4 mutant intestine. Conclusions: Our data identify GATA4 as an essential regulator of early intestinal epithelial cell proliferation. We propose that GATA4 controls proliferation in part by directly regulating transcription of cell-cycle mediators. Our data further suggest that GATA4 affects proliferation through transcriptional regulation of Fzd5, perhaps by influencing the response of the epithelium to WNT signaling. Keywords: Transcriptional Regulation, WNT Signaling, Villus Morphogenesishttp://www.sciencedirect.com/science/article/pii/S2352345X15001939 |
| spellingShingle | Bridget M. Kohlnhofer Cayla A. Thompson Emily M. Walker Michele A. Battle GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary Cellular and Molecular Gastroenterology and Hepatology |
| title | GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary |
| title_full | GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary |
| title_fullStr | GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary |
| title_full_unstemmed | GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary |
| title_short | GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in MiceSummary |
| title_sort | gata4 regulates epithelial cell proliferation to control intestinal growth and development in micesummary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X15001939 |
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