Mutations in SHH are associated with holoprosencephaly syndromes, with craniofacial malformations ranging from cyclopia to cleft lip/palate to midfacial and mandibular hypoplasia. Mouse embryos lacking Shh exhibit cyclopia and fail to form maxilla and mandible. Tissue-specific inactivation of Shh in the embryonic pharyngeal epithelium (Shhpeko) or neural crest cell-specific inactivation of Smo (Smoncko), which encodes an obligatory transducer of hedgehog signaling, results in severe micrognathia and tongue agenesis in mice. Both Shhpeko and Smoncko embryos showed increased apoptosis of neural crest cells populating the embryonic mandibular arches, but little is known about the molecular mechanisms mediating Shh signaling regulation of mandible development. We found that the Smoncko mutant embryos exhibit ectopic ossification in the oral side of the embryonic mandibular mesenchyme, leading to partial duplication of the dentary bones. Furthermore, we found that phospho-Smad1/5/9 and BMP target genes Msx1, Msx2, and Alx4, exhibit preferential expression in the aboral side of the distal mandibular arch mesenchyme in wildtype embryos but are ectopically activated in the oral side of the mandibular arch mesenchyme in Smoncko mutant embryos. Since Bmp4 is expressed in the distal mandibular arch epithelium, whereas Shh is expressed in the oral epithelium during early mandibular development, and since BMP signaling is known to regulate apoptosis and bone formation, these results suggest a crucial, but previously unappreciated, mechanism involving interactions of Shh and Bmp4 signaling pathways in patterning the oral-aboral axis of the developing mandible. We proposed two comprehensive specific aims to test the hypothesis that Shh signaling regulates the Bmp4-Msx1/2 and Bmp4-Alx4 pathways to control survival and patterning of the developing mandibular mesenchyme along the oral-aboral axis. These studies will fill a longstanding gap in the understanding of molecular mechanisms patterning the oral-aboral axis of the mammalian jaw and significantly improve our understanding of pathogenic mechanisms of mandibular developmental defects.

Public Health Relevance

Mandibular micrognathia, also known as abnormally small mandible, is a common craniofacial defect and a known cause of cleft palate. Many patients with micrognathia experience breathing and swallowing difficulties even after extensive surgical intervention, posing a significant medical burden and lifelong morbidity, but the etiology and pathogenic mechanisms of micrognathia are not well understood. Using mutant mouse models with mandibular developmental defects, this project elucidates the gene regulatory networks controlling mandible development. Information gained from these studies provide new insights into the pathogenic processes of micrognathia, and will lead to improvement in clinical care and development of better methods for treatment or prevention of such birth defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Stein, Kathryn K
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Cincinnati Children's Hospital Medical Center
United States
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