Wednesday, January 15, 2025
1/15/2025
Project Summary/Abstract Development of a functional jaw requires precise shaping of the underlying skeleton and proper integration with the musculature through tendons and ligaments. In the jaw, both the skeleton and connective tissues such as tendons and ligaments derive from multipotent cranial neural crest-derived cells (CNCCs). My project focuses on two novel mechanisms by which skeletal and connective tissue fates are balanced in the vertebrate jaw. In a previous study, we revealed that the nuclear hormone receptor Nr5a2 functions to promote connective tissue at the expense of skeletal fates in both the mouse and zebrafish jaw, yet the mechanisms by which Nr5a2 represses jaw skeleton formation were unknown. By analyzing single-cell sequencing data of nr5a2 mutants, I have identified the bile acid synthesis enzyme Hsd3b7 and the transcription factor Foxp2 as two potential targets of Nr5a2 that repress Hedgehog-dependent induction of lower jaw cartilage. In Aim 1, I test that Hsd3b7 functions as a jaw-specific repressor of Hedgehog signaling by depleting the Hedgehog co- factor cholesterol from the cell membrane of tendon-forming CNCCs. In Aim 2, I test that Foxp2 competes with the Hedgehog target Foxc1, with Foxp2 closing cartilage enhancers in the tendon-forming region of the jaw that would normally be opened by Foxc1. My research will therefore show novel and jaw-specific mechanisms by which two Nr5a2 target genes function upstream and downstream of Hedgehog signaling to pattern the region of the developing jaw generating tendons and other connective tissues. These findings will shed light on how alterations to Hedgehog regulation and chromatin accessibility may underlie human birth defects affecting jaw development. The research project and training plan for the fellowship period have been designed to lay the groundwork for my long-term goal of obtaining a position as a tenure-track professor at a top-tier academic research institution. I will receive mentorship from Dr. Gage Crump, a leading scientist in zebrafish craniofacial development. The experiments in this proposal will take place on the Health Sciences Campus of the University of Southern California, which hosts vibrant communities of craniofacial and stem cell scientists.
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