Facial epithelia, including the pharyngeal pouches, are important signaling centers that organize development of the head. Defects in pouch formation in human birth defects such as DiGeorge Syndrome result in a variety of developmental abnormalities of the facial skeleton, heart, and glands (e.g. parathyroid and thymus). However, we still know little about the genetic control and cellular behaviors underlying pouch formation. The long-term goal of this proposal is to understand how the DiGeorge Syndrome gene Tbx1 interacts with Fgf and Wnt signaling pathways to precisely control the epithelial transitions that drive pouch formation. In this proposal, we use innovative transgenic and mutant tools in zebrafish to assess the function of developmental genes in the pre-pouch endoderm. We combine this with time-lapse imaging of pouch development in living embryos, which allows us to understand how these genes control specific pouch cell behaviors. Zebrafish is ideally suited for these studies as pouch development is highly conserved with humans, yet zebrafish is the only vertebrate system in which high-throughout transgenic studies and single-cell- resolution time-lapse imaging are practical. Positive findings from this work will elucidate how Tbx1 acts upstream to activate Wnt and Fgf signaling cascades that drive pouch development. In particular, Wnt pathway genes will represent novel candidates for underlying and/or modifying human birth defects such as DiGeorge and Pfeiffer Syndromes. As branching of the embryonic endoderm generates not only pouches but also the liver, pancreas, lung, and other organs, lessons learned from our studies will also have general implications for understanding the initial formation of many important endodermal organs.

Public Health Relevance

Pharyngeal pouches are transient embryonic structures that are critical for development of the skeleton and glands of the head, as well as the heart, ear, and nervous system. Defects in pouch development underlie a number of human birth defects, such as DiGeorge Syndrome, that affect multiple organs, including the facial skeleton. The study of the genes required for the development of these pouches will therefore provide critical insights into the embryonic origins of craniofacial defects in these devastating human conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE022572-01A1
Application #
8578718
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2013-07-18
Project End
2018-05-31
Budget Start
2013-07-18
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$397,700
Indirect Cost
$155,200
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089