Facial dysmorphism induced by bone morphogenetic protein receptor type 1A-mediated signaling reduction in neural crest-derived cells

Abstract

SUMMARYBone morphogenetic protein (BMP) receptor type 1A (BMPR1A) mutations are associated with facial dysmorphism, which is one of the main clinical signs in both juvenile polyposis and chromosome 10q23 deletion syndromes. Craniofacial development requires reciprocal epithelial/neural crest (NC)-derived mesenchymal interactions mediated by signaling factors, such as BMP, in both cell populations. To address the role of mesenchymal BMP signaling in craniofacial development, we generated a conditional knockdown mouse by expressing the dominant-negative Bmpr1a in NC-derived cells expressing the myelin protein zero(Mpz)-Cre transgene. At birth, 100% of the conditional mutant mice had wide-open anterior fontanelles, and 80% of them died because of cleft face and cleft palate soon after birth. The other 20% survived and developed short faces, hypertelorism and calvarial foramina. Analysis of the NC-derived craniofacial mesenchyme of mutant embryos revealed an activation of the P53 apoptosis pathway, downregulation of both c-Myc and Bcl-XL, a normal growth rate but an incomplete expansion of mesenchymal cells. These findings provide genetic evidence indicating that optimal Bmpr1a-mediated signaling is essential for NC-derived mesenchymal cell survival in both normal nasal and frontal bone development and suggest that our model is useful for studying some aspects of the molecular etiology of human craniofacial dysmorphism.

A New Case of the Rare 10q22.3q23.2 Microdeletion Flanked by Low-Copy Repeats 3/4

“…Some of these genes, e.g., BMPR1A (601299) , LDB3 (605906), GRID1 (610659), and NRG3 (605533), have been hypothesized as putative candidate genes associated with the phenotype, especially regarding the neuropsychological development and cardiac defects [Balciuniene et al, 2007;van Bon et al, 2011;Breckpot et al, 2012]. Saito et al [2012] evaluated heart morphology of the mutant mouse knockout BMPR1A protein in neuralcrest-derived cells and showed that some of them exhibited facial fusion defects such as a cleft face and cleft palate, or facial dysmorphic features besides heart defects. Thus, the craniofacial dysmorphisms and CHD observed in our patient may be partly caused by the deletion in the BMPR1A gene.…”

A Boy with an LCR3/4-Flanked 10q22.3q23.2 Microdeletion and Uncommon Phenotypic Features

“…Other rare features are micrognathia, low-set or posteriory-rotated ears, and epicanthal folds; the patient presented here is the first one exhibiting a mediane cleft palate. In a recent publication, Saito et al [2012] presented a conditional knockout mouse model, generated by expressing a dominant negative BMPR1A protein (dnBMPR1A) in neuralcrest-derived cells (dnBMPR1A lacks the intracellular kinase domain and, thus, inhibits the BMPR1A-mediated signaling pathway). The mutant mice exhibited either facial fusion defects such as a cleft face and cleft palate, or facial dysmorphology corresponding to hypertelorism and flat nasal bridge in humans.…”

“…Reviewing literature for cases with distal chromosome 10q deletions and using computed gene prioritization, the authors showed that BMPR1A is the best candidate gene for CHD in patients with 10q22q23 deletions. Saito et al [2012] also evaluated heart morphology of the mutant animals and showed that some of those with a facial cleft exhibited a ventricular septum defect as well. Thus, deletions of BMPR1A may contribute to various phenotypes.…”

Common mechanisms in development and disease: BMP signaling in craniofacial development

“…Apoptosis due to augmented BMP signaling is seen in several craniofacial structures [35, 120, 121]. Smad-dependent BMP signaling prevents degradation of p53, and increased levels of p53 augment downstream targets, such as Bax and caspase-3 to promote apoptosis.…”