The broad objective of this proposal is to examine the roles of cdx genes and retinoic acid (RA) in regionalizing the zebrafish midgut, with particular emphasis on the pancreas and liver. RA signaling has been shown to be necessary to specify the zebrafish pancreas and liver, and the role of RA in pancreas development is conserved across vertebrates. The mechanism whereby RA functions in this context is unknown. Studies on mesoderm and ectoderm have suggested that RA functions upstream of Cdx transcription factors, which in turn signal to downstream hox genes. My preliminary experiments have established that cdx4 is required for normal pancreas localization along the digestive tract. My general strategy is to test the working hypothesis that pancreas localization relies on integrating anteriorally-derived RA signals and posteriorally-derived Cdx signals. I will investigate the roles of cdx4 and cdx2 in regionalizing the endoderm using loss-of-function approaches. Since Cdx genes have been shown to function synergistically in other systems, I will investigate whether cdx4 and cdx2 function synergistically during endoderm patterning. Using cell transplantation I will generate chimeric embryos to determine whether cdx4 influences pancreatic fate cell-autonomously versus non-cell-autonomously. Finally, I will investigate the role of RA signaling in regulating Cdx genes utilizing loss-of-function approaches as well as treatment with exogenous RA.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD050031-01
Application #
6936928
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Klein, Steven
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$48,296
Indirect Cost
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Eames, Stefani C; Philipson, Louis H; Prince, Victoria E et al. (2010) Blood sugar measurement in zebrafish reveals dynamics of glucose homeostasis. Zebrafish 7:205-13
Kinkel, Mary D; Sefton, Elizabeth M; Kikuchi, Yutaka et al. (2009) Cyp26 enzymes function in endoderm to regulate pancreatic field size. Proc Natl Acad Sci U S A 106:7864-9
Kinkel, Mary D; Prince, Victoria E (2009) On the diabetic menu: zebrafish as a model for pancreas development and function. Bioessays 31:139-52
Kinkel, Mary D; Eames, Stefani C; Alonzo, Martha R et al. (2008) Cdx4 is required in the endoderm to localize the pancreas and limit beta-cell number. Development 135:919-29