The etiology of cleft palate formation in BMP7-deficient mice

PLoS One. 2013;8(3):e59463. doi: 10.1371/journal.pone.0059463. Epub 2013 Mar 14.

Abstract

Palatogenesis is a complex process implying growth, elevation and fusion of the two lateral palatal shelves during embryogenesis. This process is tightly controlled by genetic and mechanistic cues that also coordinate the growth of other orofacial structures. Failure at any of these steps can result in cleft palate, which is a frequent craniofacial malformation in humans. To understand the etiology of cleft palate linked to the BMP signaling pathway, we studied palatogenesis in Bmp7-deficient mouse embryos. Bmp7 expression was found in several orofacial structures including the edges of the palatal shelves prior and during their fusion. Bmp7 deletion resulted in a general alteration of oral cavity morphology, unpaired palatal shelf elevation, delayed shelf approximation, and subsequent lack of fusion. Cell proliferation and expression of specific genes involved in palatogenesis were not altered in Bmp7-deficient embryos. Conditional ablation of Bmp7 with Keratin14-Cre or Wnt1-Cre revealed that neither epithelial nor neural crest-specific loss of Bmp7 alone could recapitulate the cleft palate phenotype. Palatal shelves from mutant embryos were able to fuse when cultured in vitro as isolated shelves in proximity, but not when cultured as whole upper jaw explants. Thus, deformations in the oral cavity of Bmp7-deficient embryos such as the shorter and wider mandible were not solely responsible for cleft palate formation. These findings indicate a requirement for Bmp7 for the coordination of both developmental and mechanistic aspects of palatogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 7 / deficiency
  • Bone Morphogenetic Protein 7 / genetics*
  • Cell Proliferation
  • Cleft Palate / etiology*
  • Cleft Palate / genetics
  • Cleft Palate / metabolism*
  • Embryo, Mammalian / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Mice
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Bone Morphogenetic Protein 7

Grant support

This work was supported by funds from the University of Zurich, the Swiss National Science Foundation (SNSF) (grant 31003A-135530 to D.G. and T.A.M.), and the Swiss Dental Association (SSO) for the Projects 234-07 (T.A.M.) and 255/10 (T.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.