The long-term goal of the proposed studies addresses the interplay of the cAMP and BMP-2 signaling pathways in determining the differentiation of Neural Crest (NC) cells to the sympathoadrenal (SA) lineage, employing primary NC cultures. In separate studies, bone morphogenetic proteins (BMP-2, 4 and 7) and cAMP elevating agents were shown to stimulate SA cell development, characterized by the expression of tyrosine hydroxylase (TH), dopamineB-hydroxylase (DBH) and the synthesis of catecholamines (CA). Only recently, studies from our laboratory demonstrated that the cAMP signaling pathway modulates both positive and negative signals which influence SA cell development. Specifically, moderate activation of cAMP signaling, in synergy with BMP-2, promotes SA cell development and induces the expression of the SA lineage-determining gene Phox2a. By contrast, robust activation of cAMP signaling opposes, even in the presence of BMP-2, SA cell development and blocks the expression of the SA lineage-determining genes ASH-I and Phox2a. The objectives of the proposed studies investigate the molecular mechanisms by which cAMP acts as a bimodal switch on SA cell development.
Aim 1 addresses the hypothesis that low-level cAMP signaling synergizes transcriptionally with BMP-2 signaling at the phox2a gene promoter, via synergistic interactions occurring between the transcription factors ASH-i and CREB, and the co-activator protein CBP.
Aim 2 addresses the hypothesis that the antagonistic effect of high-level cAMP signaling on SA cell development involves the activation of the MAPK pathway, effecting the inhibition of the BMP-2-activated transactivators SMADs.
The Specific Aims are:
Aim 1 : To determine whether the synergistic effect between BMP-2 and low-level activation of cAMP signaling, on SA cell development and Phox2a expression, is linked to the transcriptional function of the cAMP pathway.
Aim 2 : To define the mechanism of the antagonistic effect of high-level activation of cAMP signaling on the BMP-2 mediated ASH-I gene expression and SA cell development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK059367-01A1
Application #
6436602
Study Section
Special Emphasis Panel (ZRG1-HED-1 (01))
Program Officer
Sato, Sheryl M
Project Start
2002-02-01
Project End
2005-12-31
Budget Start
2002-02-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$290,250
Indirect Cost
Name
Purdue University
Department
Other Basic Sciences
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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