Regulation of Palate Development and Innervation

Cleft palate affects more than 1 in 1,000 children and causes significant problems in feeding, speech, increased mortality, and major challenges in social integration. In developed countries, most cleft palate patients receive surgical repair to restore an anatomically intact palate. Unfortunately, 20 – 40% of children with a repaired palate experience functional deficit known as velopharyngeal insufficiency (VPI). Many of these patients receive secondary surgery but follow-up studies often reported no significant improvement and additional complications. As increasing number of cleft patients undergo secondary surgery, VPI management remains one of the most controversial topics and a clearly unmet medical need concerning cleft palate treatment. Several authors have suggested that commonly used surgical techniques for palatoplasty could damage palatal nerve supply, contributing to VPI after cleft palate repair. However, whether deficient palatal innervation is part of cleft palate pathology and how palatal innervation is integrated with palate development are not known. We hypothesize that palatal innervation is regulated by neuronal guidance factors whose spatiotemporal expression in the developing palatal mesenchyme is regulated by resident tissue-specific transcription factors and that key guidance factors also play crucial roles in non-neuronal tissue mediated palatal morphogenesis. Interestingly, genome-wise association studies of cleft lip and palate in distinct ethnic populations have consistently detected highly significant association with variants in the netrin1 (NTN1) gene, which encodes a known important neuronal guidance factor. Ntn1 exhibits regional differential expression in the developing palatal mesenchyme and Ntn1 mutant mice exhibit cleft palate at birth. While how Ntn1 regulates palate morphogenesis is not known, we recently found that mice lacking Osr2, a key transcriptional regulator of palatal shelf growth and elevation, exhibits cleft palate associated with ectopic expression of members of the Sema3 family of repulsive axon guidance factors in the developing palatal mesenchyme and severe disruption of palatal innervation. Osr2 expression and function in the developing palatal mesenchyme integrate several key molecular pathways, including Shh-Smo signaling and the Pax9 pathways, in regulating palatal morphogenesis. We propose two specific aims to directly test our hypothesis and uncover the function and regulation of Ntn1 and Sema3 family guidance factors in palatal morphogenesis and innervation. Data from these studies will fill a longstanding critical knowledge gap regarding palate development and innervation, and provide better comprehension of cleft palate pathology that is directly applicable for improving clinical management of cleft palate treatment and patient care. Project Number: 1R01DE035481-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Yu Lan (+1 co-PI) | Institution: CINCINNATI CHILDRENS HOSP MED CTR, CINCINNATI, OH | Award Amount: $605,123 | Activity Code: R01 | Study Section: Skeletal Biology Development and Disease Study Section[SBDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11273376