Genetic pathways that promote cell-survival during development are poorly defined, yet represent potential targets for anti-cancer drugs. The genes that promote survival of melanocytes, in particular those that operate independently of the well-characterized anti-apoptotic pathway headed by the receptor tyrosine kinase, C-kit, are largely unknown. Through forward and reverse genetic studies in zebrafish, we have identified two genes that regulate the number of embryonic melanocytes independently of C-kit. One is Touchtone (Tct), which appears to prevent necrotic cell death in melanocytes, but whose molecular identity is unknown. The other is transcription factor AP-2alpha, which has long been known to be expressed in neural crest, but whose function there has remained obscure because of redundancy. Interestingly we have evidence that Tct and AP-2 are also required within neural crest-derived Rohon-Beard sensory neurons (RBs). Our overall hypothesis is that Tct and AP-2 regulate survival of neural crest derivatives, and that they may do so as part of a single regulatory pathway.
In Aim 1, to gain insight into the possibly novel Tct pathway, we propose to identify the Tct gene by positional cloning and identify new alleles.
In Aim 2, to learn the function of AP-2-type activity in neural crest and melanocytes, we propose temporal and spatial modulation of AP-2-type activity with cell-type-specific promoters.
In Aim 3, to determine the function of Tct and AP-2 in RBs, we propose ultrastructural analysis of RBs in the Tct mutant, and temporal and spatial modulation of AP-2-type activity with RB-specific promoters. Finally we propose to test for possible interaction of Tct and AP-2 type activity with double mutant experiments. These experiments exploit the advantages of the zebrafish model to dissect poorly understood neural crest regulatory pathways. These pathways are potential entry points for therapies against malignant melanoma and other neural crest diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067841-04
Application #
7389665
Study Section
Development - 1 Study Section (DEV)
Program Officer
Haynes, Susan R
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$258,736
Indirect Cost
Name
University of Iowa
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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