Tissues are formed and maintained by stem cells that produce both daughters that undergo self-renewing proliferation and daughters that differentiate. The mechanisms by which the choice between proliferation and differentiation are made are not well understood in any system. Our long-term goal is to understand how the proliferation vs. differentiation decision is made in the C. elegans germline. The GLP-1 /Notch signaling pathway induces germ cells to proliferate while GLD-1, a conserved translational represser RNA binding protein, is a key downstream differentiation factor that promotes meiotic development. Spatial control of both GLP-1/Notch signaling and GLD-1 accumulation determines the correct balance between proliferation and meiotic development in C. elegans. Notch signaling in mammals is also important in stem cell self-renewal and oncogenic Notch activation can lead to cancer. The goal of Aim 1 is to identify and characterize negative regulators of GLP-1/Notch signaling that function to limit the size of the proliferative germ cell population. Mechanisms by which Notch signaling is down-regulated are not well understood but are of general importance since there are a number of developmental contexts where activated Notch proteins must be cleared between successive rounds of Notch mediated cell fate specification (e.g. nervous system).
Aim 2 employs cell biological approaches to understand how GLP-1/Notch signaling controls proliferation over a distance of 20 cell diameters. The rise in GLD-1 levels, which is regulated by both translational activators and repressors, determines where germ cells enter meiosis and in Aim 3, additional gene products necessary for this control will be identified and characterized.
In Aim 4, mRNA targets of GLD-1 that mediate initiation of meiotic development will be identified and characterized. GLD-1 likely translationally represses these RNAs to promote meiotic development. Since little is known about activities that lead to entry into meiotic prophase in animals, results from this aim will provide an initial picture.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063310-19
Application #
7367143
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Haynes, Susan R
Project Start
1979-04-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2011-02-28
Support Year
19
Fiscal Year
2008
Total Cost
$428,468
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Chris; Wilson-Berry, Laura; Schedl, Tim et al. (2012) TEG-1 CD2BP2 regulates stem cell proliferation and sex determination in the C. elegans germ line and physically interacts with the UAF-1 U2AF65 splicing factor. Dev Dyn 241:505-21
Arur, Swathi; Ohmachi, Mitsue; Berkseth, Matt et al. (2011) MPK-1 ERK controls membrane organization in C. elegans oogenesis via a sex-determination module. Dev Cell 20:677-88
Fox, Paul M; Vought, Valarie E; Hanazawa, Momoyo et al. (2011) Cyclin E and CDK-2 regulate proliferative cell fate and cell cycle progression in the C. elegans germline. Development 138:2223-34
Rangarajan, Arun; Schedl, Tim; Yook, Karen et al. (2011) Toward an interactive article: integrating journals and biological databases. BMC Bioinformatics 12:175
Howell, Kelly; Arur, Swathi; Schedl, Tim et al. (2010) EOR-2 is an obligate binding partner of the BTB-zinc finger protein EOR-1 in Caenorhabditis elegans. Genetics 184:899-913
Hadwiger, Gayla; Dour, Scott; Arur, Swathi et al. (2010) A monoclonal antibody toolkit for C. elegans. PLoS One 5:e10161
Kerins, Jessica Amrozowicz; Hanazawa, Momoyo; Dorsett, Maia et al. (2010) PRP-17 and the pre-mRNA splicing pathway are preferentially required for the proliferation versus meiotic development decision and germline sex determination in Caenorhabditis elegans. Dev Dyn 239:1555-72
Lee, Min-Ho; Schedl, Tim (2010) C. elegans star proteins, GLD-1 and ASD-2, regulate specific RNA targets to control development. Adv Exp Med Biol 693:106-22
Dorsett, Maia; Schedl, Tim (2009) A role for dynein in the inhibition of germ cell proliferative fate. Mol Cell Biol 29:6128-39
Mantina, Pallavi; MacDonald, Lindsay; Kulaga, Adam et al. (2009) A mutation in teg-4, which encodes a protein homologous to the SAP130 pre-mRNA splicing factor, disrupts the balance between proliferation and differentiation in the C. elegans germ line. Mech Dev 126:417-29

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