Bmp-Signaling Regulates A Common Transcriptional Program to Control Facial Form and Skeletal Morphogenesis

<p>Much of the craniofacial skeleton, such as the skull vault, mandible and midface, develops through direct, intramembranous ossification of the cranial neural crest (CNC) derived progenitor cells. Bmp-signaling plays critical roles in normal craniofacial development, and Bmp4 deficiency results in craniofacial abnormalities, such as cleft lip and palate. We performed an in depth analysis of <em>Bmp4</em>, a critical regulator of development, disease, and evolution, in the CNC. Conditional <em>Bmp4</em> overexpression, using a tetracycline regulated <em>Bmp4</em> gain of function allele, resulted in facial form changes that were most dramatic after an E10.5 <em>Bmp4 </em>induction. Expression profiling uncovered a signature of Bmp4 induced genes (BIG) composed predominantly of transcriptional regulators controlling self-renewal, osteoblast differentiation, and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of <em>Bmp2</em>, <em>Bmp4</em>, and <em>Bmp7</em>, resulted in complete or partial loss of multiple CNC derived skeletal elements revealing a critical requirement for Bmp-signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss of function mutants indicating similar Bmp-regulated target genes underlying facial form modulation and normal skeletal morphogenesis. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including <em>Satb2, Smad6</em>, <em>Hand1, Gadd45</em><em>g</em> and <em>Gata3</em> that was bound by Smad1/5 in the developing mandible revealing direct, Smad-mediated regulation. These data indicate that Bmp-signaling regulates craniofacial skeletal development and facial form by balancing self-renewal and differentiation pathways in CNC progenitors.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Bonilla-Claudio, Margarita

Contributors dc:contributor

• James F. Martin, M.D., Ph.D.
• Yasuhide Furuta, Ph.D.
• Mingyao Lui, Ph.D.

• Bone morphogenetic protein
• morphogenesis
• neural crest
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/210

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1240