ArticleHuman molecular genetics2015
Lhx6 and Lhx8 promote palate development through negative regulation of a cell cycle inhibitor gene, p57Kip2.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Molecular Regulation of Palatogenesis and Clefting: An Integrative Analysis of Genetic, Epigenetic Networks, and Environmental Interactions.International journal of molecular sciences · 2025Review
- Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate.Molecular medicine (Cambridge, Mass.) · 2024Article
- Spatiotemporal Evolution of Developing Palate in Mice.Journal of dental research · 2024Article
- MicroRNAs in Small Extracellular Vesicles from Amniotic Fluid and Maternal Plasma Associated with Fetal Palate Development in Mice.International journal of molecular sciences · 2023Article
- Gene Regulatory Networks and Signaling Pathways in Palatogenesis and Cleft Palate: A Comprehensive Review.Cells · 2023Review
- Candidate positive targets of LHX6 and LHX8 transcription factors in the developing upper jaw.Gene expression patterns : GEP · 2022Article
- Article
- Temporal induction of Lhx8 by optogenetic control system for efficient bone regeneration.Stem cell research & therapy · 2021Article
- Lhx6 regulates canonical Wnt signaling to control the fate of mesenchymal progenitor cells during mouse molar root patterning.PLoS genetics · 2021Article
- The Bone-Forming Properties of Periosteum-Derived Cells Differ Between Harvest Sites.Frontiers in cell and developmental biology · 2020Article
- Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts.American journal of medical genetics. Part A · 2019Article
- Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway.Cellular signalling · 2018Article
- Molecular and Cellular Mechanisms of Palate Development.Journal of dental research · 2017Review
- Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.Scientific reports · 2017Article
- LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of β-catenin.Journal of Cancer · 2017Article
- Expression of forkhead box transcription factor genes Foxp1 and Foxp2 during jaw development.Gene expression patterns : GEP · 2016Article
- Using frogs faces to dissect the mechanisms underlying human orofacial defects.Seminars in cell & developmental biology · 2016Review
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Authors and funding
10 authors at 3 institutions in 1 country.
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Abstract
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.
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