Title: Defining regulatory networks in orofacial morphogenesis and cleft lip pathogenesis
Abstract: Cleft lip, one of the most common structural birth defects, results from deficient outgrowth of the medial nasal process (MNP) the forms the philtrum of the upper lip. However, the developmental mechanisms underlying cleft lip pathogenesis remain poorly understood. Utilizing a mouse model of cleft lip caused by transient Sonic hedgehog (Shh) signaling disruption, we integrated bulk and single cell RNA sequencing to define cellular and molecular changes underlying impaired MNP outgrowth. Transcriptomic analyses of the MNP at gestational day (GD)11, during upper lip closure, revealed altered cell fate specification with reductions in Shh-responsive and chondrogenic populations and expansion of uncommitted, neural-like, and Wnt signaling-responsive osteoprogenitor states. We also investigated whether prenatal folic acid supplementation, a dietary methyl donor, could prevent clefting caused by Shh pathway disruption. Maternal folic acid supplementation reduced cleft severity in this model based on morphometric measurements taken during upper lip closure. Integrated methylomic and transcriptomic analyses of the GD11 MNP identified FA-responsive changes in key Shh pathway genes including Shh, Foxa1, Pax6, and Thy1. Together, our findings identify transcriptional, cellular, and epigenetic mechanisms linking disrupted developmental signaling and environmental factors to orofacial cleft risk, providing a foundation for mechanism-based prevention strategies.
Join Zoom Meeting
https://uwmadison.zoom.us/j/91814162149?pwd=AYgwgbFNekOLHyQrj7wUCkxem9b2Yw.1
Meeting ID: 918 1416 2149
Passcode: 970506