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.
Highlights
Bone morphogenetic proteins (Bmps) function via conserved type 1 and type 2 transmembrane receptors to regulate a range of biological processes, including cell proliferation, apoptosis, differentiation and cell shape, in a highly context-dependent manner (Massagué, 2000; Chen et al, 2004; Aubin et al, 2004; Kishigami and Mishina, 2005; Eblaghie et al, 2006)
Facial abnormalities and heart septal defects in human patients may be partly caused by the knockdown of BMPR1A-mediated signaling in neural crest (NC)-derived cells
Compared to our double-tg mice, 2 previous mutant mice lacking Bmp receptor 1a (Bmpr1a) in NC cells exhibited more severe heart septal defects (Nomura-Kitabayashi et al, 2009; Stottmann et al, 2004) that correlated with the level of Bmpr1a-mediated signaling
Summary
Bone morphogenetic proteins (Bmps) function via conserved type 1 and type 2 transmembrane receptors to regulate a range of biological processes, including cell proliferation, apoptosis, differentiation and cell shape, in a highly context-dependent manner (Massagué, 2000; Chen et al, 2004; Aubin et al, 2004; Kishigami and Mishina, 2005; Eblaghie et al, 2006). Vertebrate facial development starts with the emergence of 5 facial primordia: a frontonasal prominence and paired maxillary and mandibular processes. These primordia mainly consist of neural crest (NC)-derived mesenchyme covered by epithelium (Chai and Maxon, 2006). While the processes grow out in conjunction with regulated mesenchymal cell proliferation and apoptosis (Minkoff, 1980; Beverdam et al, 2001), paired lateral and medial nasal processes bilaterally bulge at the frontonasal prominence. 2 died in the late embryonic stage and the other displayed no recombination in the mesenchymal cells of the nasal processes To overcome these issues, here, we established a new Bmpr1a-mediated signaling knockdown mouse line in NC cells and confirmed that the signal is involved in craniofacial developmental processes
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