The long term goal of this project is to advance our understanding of the cellular and molecular mechanisms that control neural crest development. Neural crest cells are vertebrate-specific, appear early in development, migrate extensively and differentiate into several derivatives, including: craniofacial components (muscle and cartilage amongst others), peripheral nervous system and melanocytes of the skin. Defects in neural crest development and homeostasis result in human pathologies or "neurocristopathies" that include cleft lip/palate, Waardenburg syndrome, and melanoma, amongst others. Advancing our understanding of the biology of neural crest cells is fundamental to aid in diagnostic and therapeutic approaches. This project investigates early stages of neural crest formation, and focuses on the contributions made by signaling pathways. This work centers in two models - the avian embryo and a novel model of human neural crest development based on human embryonic stem cells. In the chick we utilize blastula embryos, while in the human stem cell model we address the earliest time points of differentiation. In both models, the role of Wnt and FGF signaling pathways will be scrutinized.
Aim 1 is directed to elucidate the specific contributions made by distinct FGF-signaling branches during blastula and gastrula stages, and to establish differential responses and transcriptional effectors of FGF signaling.
Aim 2 dissects the contributions made by the dominant canonical and alternative non- canonical Wnt pathways.
Aim 3 will establish the contributions made by these two signaling pathways (FGF, Wnt) to human neural crest development using an efficient and robust model based in human embryonic stem cells. This work will illuminate fundamental principles of neural crest formation in higher vertebrates (birds and mammals), and will invigorate human neural crest studies.

Public Health Relevance

Neural crest cells contribute to a wide range of derivatives, and their aberrant development is responsible for many human pathologies. This project is designed to reveal basic principles of neural crest development in both avian embryos and in a model of human neural crest development. The project focuses on signaling mechanisms (FGF and Wnt) during early stages of neural crest development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DE017914-06
Application #
8729719
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Scholnick, Steven
Project Start
2006-10-01
Project End
2014-08-31
Budget Start
2013-09-18
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$333,000
Indirect Cost
$133,000
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520