The neural crest (NC) is a stem cell population that originates within the forming central nervous system. NC cells delaminate from the neuroepithelium by undergoing a spatiotemporally regulated epithelial-to- mesenchymal transition (EMT) that proceeds in a coordinated wave head-to-tail to exit from the neural tube. Cranial NC cells, which arise in the head region of the embryo and are the only NC population in vivo with the ability to differentiate into craniofacial skeleton and cartilage, are indispensable for the development of the face; mutations affecting NC development result in numerous diseases and malformations affecting the craniofacial structures (e.g. Treacher Collins syndrome, cleft palate, etc.). Thus, a thorough understanding of the regulation of cranial NC EMT is essential to identify the etiology of craniofacial abnormalities. To date, research has focused on unraveling early events governing cranial NC induction at the neural plate border and the mechanism of delamination from the neural tube. However, little is known about the regulatory changes governing the timing of NC EMT and exit from the neural tube. My preliminary studies demonstrate that a Wnt pathway antagonist, Draxin, plays an important role in controlling the timing of NC EMT, perturbations of which have negative consequences for cranial NC migration. This role for Draxin is particularly interesting in light of the fact that the Wnt signaling pathway has been shown to be a major driver of NC development. The goal of this Proposal is to investigate the molecular mechanism by which Draxin affects cranial NC EMT, with focus on its role in Wnt signaling. To this end, the Specific Aims of this Proposal seek to combine chick embryology with state-of-the-art imaging and biochemistry to: 1) Characterize the interaction of Draxin and Wnt signaling in cranial NC EMT; 2) Identify the role of Draxin in the regulation of cell adhesion proteins; 3) Characterize the post-transcriptional regulation of Draxin; and 4) Identify the role of Draxin in the regulation of extracellular matrix proteins. The results of this Proposal will significantly enhance our understanding of the regulation of cranial NC EMT and migration, providing new scientific avenues for translational research applications in the treatment of craniofacial defects.

Public Health Relevance

PUBLIC HEALTH RELEVANCE: Defects in cranial neural crest development lead to a variety of craniofacial diseases and malformations affecting the face, e.g. Treacher Collins syndrome, DiGeorge syndrome, and cleft palate to name a few. In this project, I will investigate the regulation and mechanism of function of the secreted protein Draxin, which will significantly enhance our understanding of the regulation of cranial neural crest delamination and migration, providing new scientific avenues for translational research applications in the treatment of craniofacial defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Career Transition Award (K99)
Project #
5K99DE028592-02
Application #
9949694
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2019-07-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125