The feature that sets the nervous system apart from other tissues is the complexity of its cell network. This complexity is founded on the great diversity of neurons that populate a functional nervous system. Asymmetric cell divisions, in which a precursor cell divides to produce two sibling cells of distinct fates, play a central role in generating the cellular diversity found in both vertebrate and invertebrate nervous systems. Research in Drosophila has begun to elucidate the genetic and molecular basis of asymmetric divisions. These data indicate that the Notch signaling pathway acts in opposition to the membrane-associated protein Numb to mediate the asymmetric division of neural (and muscle) precursors. The present model is that Numb is asymmetrically segregated during precursor division into one sibling where it blocks Notch signaling and allows this cell to adopt the CEB1fate. The other sibling, which lacks Numb protein, receives active Notch input and adopts the CEA1cell fate. In this manner, the Notch/Numb cassette mediates the binary cell fate choice of most if not all sibling CNS neurons. Through a genetic screen we identified sanpodo as a gene that acts with the Notch pathway to mediate asymmetric divisions, sanpodo was initially characterized as the homolog of the vertebrate gene encoding the F-actin/tropomyosin binding protein, Tropomodulin. However, our data provide compelling evidence that sanpodo does not encode Tropomodulin but rather a novel four-pass transmembrane protein. The goals of this proposal are to elucidate the genetic and molecular basis through which sanpodo mediates asymmetric divisions. Specifically, we propose: (1) to confirm the molecular identity of sanpodo; (2) to complete a systematic genetic, expression and molecular analysis of sanpodo; and (3) to elucidate the molecular mechanism by which sanpodo regulates asymmetric divisions by identifying Sanpodo-interacting proteins. Mammalian homologs of Notch pathway members and numb exist. Recent genetic, expression and molecular studies suggest these factors also regulate asymmetric divisions in mammals. Thus, the elucidation of how Sanpodo function integrates with that of Notch and Numb to regulate asymmetric cell divisions is likely to provide general insights into the molecular and genetic mechanisms that create cell diversity throughout animal development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068048-02
Application #
6741914
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Carter, Anthony D
Project Start
2003-05-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$229,500
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Das Thakur, Meghna; Feng, Yunfeng; Jagannathan, Radhika et al. (2010) Ajuba LIM proteins are negative regulators of the Hippo signaling pathway. Curr Biol 20:657-62
Babaoglan, A Burcu; O'Connor-Giles, Kate M; Mistry, Hemlata et al. (2009) Sanpodo: a context-dependent activator and inhibitor of Notch signaling during asymmetric divisions. Development 136:4089-98
O'Connor-Giles, Kate M; Skeath, James B (2003) Numb inhibits membrane localization of Sanpodo, a four-pass transmembrane protein, to promote asymmetric divisions in Drosophila. Dev Cell 5:231-43