Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development.
We performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmp-regulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Margarita
M
Bonilla-Claudio
Jun
J
Wang
Yan
Y
Bai
Elzbieta
E
Klysik
Jennifer
J
Selever
James F
JF
Martin
D000818:Animals; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005147:Facial Bones / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008334:Mandible / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D009432:Neural Crest / Q000166:cytology / Q000502:physiology*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D012886:Skull / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014158:Transcription, Genetic
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7