# Mandible Development

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $641,646

## Abstract

Abstract
 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.

## Key facts

- **NIH application ID:** 10194460
- **Project number:** 5R01DE027046-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** RULANG JIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $641,646
- **Award type:** 5
- **Project period:** 2017-07-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194460

## Citation

> US National Institutes of Health, RePORTER application 10194460, Mandible Development (5R01DE027046-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10194460. Licensed CC0.

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