Craniofacial malformations resulting from genetic alterations and/or environmental insults are among the most common forms of human birth defects. Exquisite epithelial-mesenchymal and epithelial- epithelial interactions are critical for growth, patterning, and fusing of the facial prominences/swellings during formation of complex craniofacial structures. Therefore, understanding the underlying molecular mechanisms of these interactions is of paramount importance in understanding facial morphogenesis and pathogenesis. The overall goal of the proposed studies is to identify epithelial signals that regulate facial morphogenesis and ultimately to establish molecular targets of therapeutics for craniofacial anomalies. In contrast to the cranial neural crest-derived mesenchymal cells, which form most facial skeletal structures, relatively little is known about the epithelial contributions to craniofacial morphogenesis. Our preliminary studies demonstrate that epithelial-specific manipulations of the Wnt/? -catenin signaling pathway result in severe facial malformations, including jaw dysmorphism and the cleft lip and/or palate (CL/P). Based on these findings, we hypothesize that the epithelial Wnt/? -catenin signal pathway is the critical inducer of mammalian facial topology. We propose two complementary specific aims to test the hypothesis. First, to uncover the mechanisms by which epithelial ?-catenin controls mesenchymal cell fate during jaw formation;second, to elucidate the epithelial-specific signaling mechanisms of mammalian middle face morphogenesis.

Public Health Relevance

Craniofacial malformations resulting from genetic alterations and/or environmental insults are among the most common forms of human birth defects. Accordingly, understanding the underlying molecular mechanisms of epithelial signaling is of paramount importance in understanding facial morphogenesis and pathogenesis. The overall goal of the proposed studies is to identify epithelial signals that regulate facial morphogenesis and ultimately to establish molecular targets of therapeutics for craniofacial anomalies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019823-04
Application #
8268925
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2009-05-13
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$426,344
Indirect Cost
$181,319
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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