Lab Projects

Palate Development and Palatal Innervation

Cleft palate is one of the most common structural birth defects in humans. Most cleft palate patients in developed countries receive surgical repair and reconstruction of the palate, which restores many of the crucial functions of the palate but about 30% of these children still experience velopharyngeal dysfunction (VPD) and impairment of speech and/or hearing after treatment. Through mouse genetic studies, we identified the zinc finger transcription factor OSR2 as a key regulator of palate development and patterning. Combined analyses of genome-wide OSR2 binding, chromatin accessibility, and differential gene expression in the control and Osr^2-/- embryos revealed that expression of several Sema3 family genes were aberrantly increased in the absence of OSR2. Immunofluorescent detection of nerve fibers revealed that Osr2 mutants exhibited disruption of palatal innervation, suggesting that OSR2 regulates palatal innervation through controlling the patterns of Sema3 gene expression. We have generated mice with disruptions in Sema3a, Sema3d, or both, using CRISPR/Cas9-mediated genome editing, and found that Sema3a and Sema3d play partly redundant roles in regulating craniofacial innervation.

Regulation of Palatal Muscle Development

Humans have five pairs of palatal muscles that all attach to the palatine aponeurosis, a fan-like dense fibrous connective tissue comprising the core of the soft palate linking palatal muscles to the hard palate bones. Patients with partial cleft of the soft palate or submucous cleft palate suffer from velopharyngeal insufficiency with speech and hearing impairment due to misconnections of the palatal muscles. We found that mice lacking Foxd1 die shortly after birth with air-filled stomach. Histological studies revealed that Foxd1^-/- mice exhibit partial cleft of the soft palate with most of the tensor veli palatini (TVP) muscles misattached to the lateral side of the pterygoid process rather than to the palatine aponeurosis. To unravel the cellular and molecular mechanisms controlling palatal muscle formation and musculoskeletal tissue integration crucial for palatal function, we have generated a new Foxd1 conditional mouse line to systematically dissect and delineate the molecular pathways involving Foxd1 in regulating the muscle-connective tissue interactions.