The Etiology of Cleft Palate Formation in BMP7-Deficient Mice

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.

Dislocated Tongue Muscle Attachment and Cleft Palate Formation

“…by a malformed lower jaw. Indeed, at the stage of palatal shelf elevation (E14.5) these embryos present with micrognathia and unfused Meckel's cartilages (Kouskoura et al 2013 (Fig. 1A, B).…”

“…However, when isolated Bmp7-deficient E13.5 maxillae or palatal shelves were grown in culture, shelf elevation (Supplementary Fig. 1) and fusion (Kouskoura et al 2013) appeared to occur quite normally.…”

“…At E14.5, Meckel's cartilages were fused in a prominent rostral process in the wildtype, but remained unfused in Bmp7 Δ/Δ embryos (not shown; c.f. Kouskoura et al 2013). …”

“…Since we could not detect any obvious defects in proliferation and growth of the palatal shelves and in their ability to fuse in vitro in our mouse model (Kouskoura et al 2013), we investigated how severe micrognathia might disturb palatal shelf elevation. We found that in the absence of Bmp7, an altered development and morphology of Meckel`s cartilage causes specific displacements of the attachment sites of the genioglossus muscle, thus disturbing its function in tongue protrusion.…”

DLX1 and MMP3 contribute to oral clefts with and without positive family history of cancer

“…Studies have shown that BMP2, BMP4, and BMP7 genes are expressed during embryogenesis of the many structures in the orofacial complex. [13][14][15] In recent years, evidence has accumulated of BMPs' important functions in tumour development. 16,17 DLX genes constitute a family of homeobox transcription factors involved in control of cell differentiation and morphogenesis.…”