Cleft palate is among the most common birth defects in humans. We and others have shown that transforming growth factor-?3 (Tgf-?3) plays a critical role in palatal epithelial fusion both in mice and in humans. Failure in Tgf-?3 signaling leads to a condition in which the palatal medial edge epithelium fails to disappear, and subsequently fully- grown palatal shelves fail to fuse. During previous funding years of this grant, we have shown that Tgf-? signaling is required both in the palatal epithelium and in the palatal mesenchyme for appropriate palatal shelf growth, patterning and fusion. Consequently, our results suggest that the role of Tgf-?3 during palatogenesis is broader and more complex than previously thought. Based on the recent findings and our preliminary data, we have formulated an overall hypothesis that specific, modular, long-distance regulatory elements are responsible of targeting Tgf?3 expression to the prefusion palatal epithelium. This epithelial-specific expression of Tgf?3, in turn, induces both Smad4-dependent (canonical) and Smad4-independent (non-canonical) signaling events in the palatal epithelium that are together with the mesenchymal Tgf-?3 signaling, required for successful palatal fusion.
In specific aim 1, we propose to test the hypothesis that Tgf?3 transcription in palatal medial edge epithelial cells is regulated by distant 5'and/or 3'enhancers.
In specific aim 2, we propose to test the hypothesis that Tgf-?-activated kinase-1 (Tak1) functions together with the Smad4-mediated signaling pathway to induce Tgf-?3-induced cell cycle arrest and subsequent apoptosis in palatal epithelial cells.
In specific aim 3, we propose to test the hypothesis that in Tgfb3 null mutants, imbalance between Tgf-? and Notch signaling leads to an attenuated expression of cell cycle inhibitors ultimately resulting in cleft palate, and finally, in specific aim 4, we propose to test the hypothesis that Tgf-?3 plays a previously unexpected role in the palatal mesenchyme by regulating appropriate patterning of prefusion palatal shelves. Our unique experimental models and state-of-art strategy will allow us to define to the role of canonical and non-canonical Tgf-? signaling during palatogenesis. Collectively, the proposed experiments are likely to be of critical importance in attempting to understand the molecular basis of the cleft palate syndrome in humans.

Public Health Relevance

Cleft palate is one of the most common congenital birth defects in humans. The proposed studies dissect the role of a transforming growth factor-beta signaling in the pathogenesis of cleft palate. We expect that the proposed studies will be important in understanding of the underlying molecular mechanisms that lead to the cleft palate syndrome in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013085-13
Application #
8230752
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2001-02-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
13
Fiscal Year
2012
Total Cost
$416,319
Indirect Cost
$136,949
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Lane, Jamie; Yumoto, Kenji; Pisano, Justin et al. (2014) Control elements targeting Tgfb3 expression to the palatal epithelium are located intergenically and in introns of the upstream Ift43 gene. Front Physiol 5:258
Lane, Jamie; Kaartinen, Vesa (2014) Signaling networks in palate development. Wiley Interdiscip Rev Syst Biol Med 6:271-8
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