Prolonged Progenitor Maintenance Sculpts the Upper Face Though dozens of genes are known to participate in shaping the facial skeleton, how facial skeletal precursors are differentially allocated into cartilage versus bone fates in different parts of the face remains poorly understood. Dr. Mork's postdoctoral work in Dr. Gage Crump's lab at USC offers a new perspective on how the vertebrate skull is built, where prolonged maintenance of skeletal progenitors appears to underlie the increased proportion of directly-ossifying dermal bone relative to cartilage in the upper versus the lower face. Importantly for public health, many common craniofacial birth defects affecting various parts of the skull, including craniosynostosis, cleft palate, and middle ear bone abnormalities, could potentially be explained by precocious differentiation of skeletal progenitors.
The aims outlined in this proposal take genetic and developmental approaches in zebrafish and mouse models, combined with sophisticated live-imaging and genome-wide expression analyses, to substantiate this new model of facial patterning. The proposed experiments will build from her extensive preliminary data to test the hypothesis that two novel targets of the key differentiation- suppressing Jagged-Notch pathway ? Fibroblast Growth Factor 20 (Aim 1) and Nuclear Receptor 2f genes (Aims 2 & 3) ? actively maintain cells in a progenitor state in the upper face of the developing embryo, thereby preserving dermal bone precursors at the expense of cartilage differentiation in the upper facial skeleton.
Aims 1 & 3 will be initiated under the mentorship of Drs. Crump and Chai and completed during the R00 period, whereas Aim 2 is farther along and will be completed before the end of the K99 phase. This project has been designed to facilitate Dr. Mork's career goal of obtaining a position as a tenure-track Assistant Professor at a top-tier academic research institution. She plans to develop an independent research program relying on state-of-the-art genetic and imaging methods in both zebrafish and mouse models to address unresolved questions in craniofacial developmental biology with clear relevance for human health. During the K99 phase, she will benefit from continued mentorship in zebrafish development by Dr. Crump, crucial training in mouse craniofacial biology from her co-mentor Dr. Yang Chai, and additional career and scientific guidance at regularly scheduled meetings with her full Advisory Committee. Additional career development activities at USC, such as grant-writing and mentorship workshops, will prepare Dr. Mork for the transition to an independent faculty position during the R00 phase. As USC hosts one of the most experienced and thriving communities of craniofacial and skeletal biologists in the country, there are few better places that she could acquire the training, resources, and network of collaborators needed to establish herself as an independent investigator in craniofacial biology.
This proposal addresses the novel hypothesis that the upper and lower face acquire their distinct bone and cartilage compositions as a result of prolonged maintenance of skeletal stem cells in the upper face of the developing embryo. The findings generated from this project will provide a fresh perspective into how precocious skeletal differentiation may contribute to common human craniofacial birth defects, in line with the mission of the NIDCR.