title: Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression.
abstract: Craniofacial development is characterized by reciprocal interactions between neural crest cells and neighboring cell populations of ectodermal, endodermal and mesodermal origin. Various genetic pathways play critical roles in coordinating the development of cranial structures by modulating the growth, survival and differentiation of neural crest cells. However, the regulation of these pathways, particularly at the epigenomic level, remains poorly understood. Using murine genetics, we show that neural crest cells exhibit a requirement for the class I histone deacetylase Hdac3 during craniofacial development. Mice in which Hdac3 has been conditionally deleted in neural crest demonstrate fully penetrant craniofacial abnormalities, including microcephaly, cleft secondary palate and dental hypoplasia. Consistent with these abnormalities, we observe dysregulation of cell cycle genes and increased apoptosis in neural crest structures in mutant embryos. Known regulators of cell cycle progression and apoptosis in neural crest, including Msx1, Msx2 and Bmp4, are upregulated in Hdac3-deficient cranial mesenchyme. These results suggest that Hdac3 serves as a critical regulator of craniofacial morphogenesis, in part by repressing core apoptotic pathways in cranial neural crest cells.
authors.affiliation: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Singh
authors.forename: Mudit
authors.initials: M
authors.lastname: Gupta
authors.forename: Chinmay M
authors.initials: CM
authors.lastname: Trivedi
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D019465:Craniofacial Abnormalities / Q000235:genetics*; D005145:Face / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006652:Histological Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051957:MSX1 Transcription Factor / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D009432:Neural Crest / Q000196:embryology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000196:embryology*; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D051957:MSX1 Transcription Factor; D000099186:Histone Deacetylase 3; C484084:Msx1 protein, mouse