Segmentation is the process that produces a metameric pattern of somites during embryonic development. This segmental pattern of organization is critical for the subsequent development of structures such as the vertebral column, associated spinal nerves, muscles and other tissues. Defects in this process during development leads to vertebral column abnormalities, such as that observed in spondylocostal dysostosis syndrome in humans. A key process that is required for this segmental patterning is a segmentation clock that is mediated by the Notch pathway. Expression of genes in this pathway oscillate on and off during each segmental cycle, specifying the boundaries between each segment by regulating the segmental expression of transcription factors. The key role of the Notch pathway in this process is indicated in part by the observation that the spondylocostal dysostosis syndrome in humans is linked to a haploinsufficiency in the human Delta3-like gene, which encodes a ligand in the Notch pathway. The goal of this application is to determine the molecular bases of the segmentation clock. The experiments proposed will dissect the genetic regulatory elements that are required for generating oscillations in the expression of Notch pathway genes in Xenopus embryos where segmentation occurs. Other experiments will examine how the output of these oscillations regulates segmental gene expression. Finally experiments are proposed to identify small molecules that disrupt these oscillations, as well as other genes required for the oscillations to occur. Results from these experiments will generate basic knowledge about a developmental mechanism that is key to the formation of the vertebrate body plan, including that of humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037266-08
Application #
7011197
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Javois, Lorette Claire
Project Start
1999-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
8
Fiscal Year
2006
Total Cost
$330,096
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kim, S H; Jen, W C; De Robertis, E M et al. (2000) The protocadherin PAPC establishes segmental boundaries during somitogenesis in xenopus embryos. Curr Biol 10:821-30