Lhx6andLhx8promote palate development through negative regulation of a cell cycle inhibitor gene,p57Kip2
| العنوان: | Lhx6andLhx8promote palate development through negative regulation of a cell cycle inhibitor gene,p57Kip2 |
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| المؤلفون: | Daniel Vogt, Yangu Zhao, André Landin Malt, John L.R. Rubenstein, Zuojian Tang, Juhee Jeong, Jeffry M. Cesario, Magnus Sandberg, Stuart M. Brown, Lindsay J. Deacon |
| المصدر: | Human Molecular Genetics. 24:5024-5039 |
| بيانات النشر: | Oxford University Press (OUP), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Transcriptional Activation, medicine.medical_specialty, Genotype, Organogenesis, LIM-Homeodomain Proteins, Gene Expression, Nerve Tissue Proteins, Biology, Mice, Molecular genetics, Maxilla, Genetics, medicine, Animals, Humans, Cyclin-Dependent Kinase Inhibitor p57, Molecular Biology, Transcription factor, Genetics (clinical), Cell Proliferation, Regulation of gene expression, Palate, Cell growth, Gene Expression Profiling, Gene Expression Regulation, Developmental, Forkhead Transcription Factors, Articles, General Medicine, Cell cycle, Cell biology, Repressor Proteins, Gene expression profiling, Mutation, Homeobox, Chromatin immunoprecipitation, Genome-Wide Association Study, Protein Binding, Transcription Factors |
| الوصف: | Cleft palate is a common birth defect in humans. Therefore, understanding the molecular genetics of palate development is important from both scientific and medical perspectives. Lhx6 and Lhx8 encode LIM homeodomain transcription factors, and inactivation of both genes in mice resulted in profound craniofacial defects including cleft secondary palate. The initial outgrowth of the palate was severely impaired in the mutant embryos, due to decreased cell proliferation. Through genome-wide transcriptional profiling, we discovered that p57(Kip2) (Cdkn1c), encoding a cell cycle inhibitor, was up-regulated in the prospective palate of Lhx6(-/-);Lhx8(-/-) mutants. p57(Kip2) has been linked to Beckwith-Wiedemann syndrome and IMAGe syndrome in humans, which are developmental disorders with increased incidents of palate defects among the patients. To determine the molecular mechanism underlying the regulation of p57(Kip2) by the Lhx genes, we combined chromatin immunoprecipitation, in silico search for transcription factor-binding motifs, and in vitro reporter assays with putative cis-regulatory elements. The results of these experiments indicated that LHX6 and LHX8 regulated p57(Kip2) via both direct and indirect mechanisms, with the latter mediated by Forkhead box (FOX) family transcription factors. Together, our findings uncovered a novel connection between the initiation of palate development and a cell cycle inhibitor via LHX. We propose a model in which Lhx6 and Lhx8 negatively regulate p57(Kip2) expression in the prospective palate area to allow adequate levels of cell proliferation and thereby promote normal palate development. This is the first report elucidating a molecular genetic pathway downstream of Lhx in palate development. |
| تدمد: | 1460-2083 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bb2023e6596a6e80b114b48ee1dbd164 https://doi.org/10.1093/hmg/ddv223 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bb2023e6596a6e80b114b48ee1dbd164 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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