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

Abstract

SUMMARYWe 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 Bmpregulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45 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.

The Pitx2:miR-200c/141:noggin pathway regulates Bmp signaling and ameloblast differentiation

“…4E). Bmpr1a encodes a type I Bmp receptor that is expressed in the dental and palate epithelium and mesenchyme at early stages of development and mediates phosphorylation of Smad1 (Bonilla-Claudio et al, 2012;He et al, 2010). Importantly, in LS-8 cells transfected with miR200c, qPCR analysis indicated increased Amel expression, a gene known to be responsive to Bmp in the dental epithelium and a marker for differentiated dental epithelial cells (Fig.…”

Bmp signaling repressesVegfato promote outflow tract cushion development

“…Bmp2, Bmp4 and Bmp7 show overlapping expression patterns and functional redundancy (Bonilla-Claudio et al, 2012;Dudley and Robertson, 1997;Furuta et al, 1997;Wang et al, 2010). We compared their expression patterns using lacZ knock-in mouse lines for Bmp2 and Bmp4 and in situ hybridization of Bmp7.…”

Bmp2 gene in osteoblasts of periosteum and trabecular bone links bone formation to vascularization and mesenchymal stem cells

“…The bone morphogenic protein (BMP) signaling pathway is important for developmental and postnatal physiological processes (Bonilla-Claudio et al, 2012;Dutko and Mullins, 2011;Sieber et al, 2009;Watabe and Miyazono, 2009;Yoon et al, 2005;Zhao et al, 2002). BMP signaling pathways are common for BMP ligands and involve three different type I BMP receptors and two different type II receptors plus negative regulators of BMP signaling, such as noggin and gremlin (Dutko and Mullins, 2011).…”