Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development

Development. 2012 Feb;139(4):709-19. doi: 10.1242/dev.073197. Epub 2012 Jan 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 2 / metabolism
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • Bone Morphogenetic Protein 7 / genetics
  • Bone Morphogenetic Protein 7 / metabolism
  • Cell Differentiation / physiology
  • Embryo, Mammalian / anatomy & histology
  • Embryo, Mammalian / physiology
  • Facial Bones* / anatomy & histology
  • Facial Bones* / embryology
  • Facial Bones* / growth & development
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Humans
  • Mandible* / anatomy & histology
  • Mandible* / embryology
  • Mandible* / growth & development
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Morphogenesis / physiology
  • Neural Crest / cytology
  • Neural Crest / physiology*
  • Sequence Alignment
  • Signal Transduction / physiology*
  • Skull* / anatomy & histology
  • Skull* / embryology
  • Skull* / growth & development
  • Stem Cells / cytology
  • Stem Cells / physiology
  • Transcription, Genetic*

Substances

  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein 7