A central problem in metazoan development is how cells are governed to grow or differentiate in a tissue-specific pattern. We propose to analyze the genetic and molecular basis of this fundamental problem in the germ line of the nematode Caenorhabditis elegans. The C. elegans germ line is particularly suitable for these studies because of its powerful genetics, completed genome sequence, and cellular simplicity. A single somatic regulatory cell serves as a """"""""niche"""""""" for germline stem cells, and this cell promotes germline proliferation by the conserved GLP-1/Notch signaling pathway. Moreover, the mitosis/meiosis decision is controlled, at least in part, by RNA-binding proteins of four conserved classes (Puf, Nanos, STAR/quaking, Bic-C) plus a newly discovered cytoplasmic poly(A) polymerase. In the next five years, we propose to analyze mechanisms by which central players of germline control (GLP-1 signaling/RNA regulators) are able to orchestrate growth of the germ line and specification of the mitosis/meiosis decision. First, we will identify genes directly controlled by GLP-1 signaling to promote germline mitoses. This work is predicted to link GLP-1 signaling with the RNA regulatory network and perhaps with the cell cycle machinery driving mitosis. Second, RNA regulators will be analyzed with respect to their relationship to GLP-1 signaling, their relationships among each other and their target mRNAs. This work is predicted to delineate the backbone of the genetic circuit controlling germline growth and the switch into the meiotic cell cycle. Third, additional regulators will be identified and investigated to learn their genetic and molecular relationships with the known central players. To this end, we propose to combine bioinformatics, RNAi and traditional genetics. Fourth, the nature of germline stem cells within the germline mitotic region will be investigated. Finally, the molecular circuit controlling germline growth and differentiation will be linked to cellular behaviors in the mitotic germ line, including cell cycle progression and tissue shape. The proposed studies will serve as a paradigm for developmental controls in higher organisms, including humans. The health-relatedness of this work is two-fold. First, the germ line holds the key to fertility. Second, germline stem cells may be the ultimate source of stem cells for tissue replacement in diseased or injured individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069454-03
Application #
7006630
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$212,401
Indirect Cost
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Noble, Daniel C; Aoki, Scott T; Ortiz, Marco A et al. (2016) Genomic Analyses of Sperm Fate Regulator Targets Reveal a Common Set of Oogenic mRNAs in Caenorhabditis elegans. Genetics 202:221-34
Friend, Kyle; Brooks, Hunter A; Propson, Nicholas E et al. (2015) Embryonic Stem Cell Growth Factors Regulate eIF2? Phosphorylation. PLoS One 10:e0139076
Byrd, Dana T; Knobel, Karla; Affeldt, Katharyn et al. (2014) A DTC niche plexus surrounds the germline stem cell pool in Caenorhabditis elegans. PLoS One 9:e88372
Sorokin, Elena P; Gasch, Audrey P; Kimble, Judith (2014) Competence for chemical reprogramming of sexual fate correlates with an intersexual molecular signature in Caenorhabditis elegans. Genetics 198:561-75
Kershner, Aaron M; Shin, Heaji; Hansen, Tyler J et al. (2014) Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance. Proc Natl Acad Sci U S A 111:3739-44
Ortiz, Marco A; Noble, Daniel; Sorokin, Elena P et al. (2014) A new dataset of spermatogenic vs. oogenic transcriptomes in the nematode Caenorhabditis elegans. G3 (Bethesda) 4:1765-72
Kershner, Aaron; Crittenden, Sarah L; Friend, Kyle et al. (2013) Germline stem cells and their regulation in the nematode Caenorhabditis elegans. Adv Exp Med Biol 786:29-46
LeGendre, Jacqueline Baca; Campbell, Zachary T; Kroll-Conner, Peggy et al. (2013) RNA targets and specificity of Staufen, a double-stranded RNA-binding protein in Caenorhabditis elegans. J Biol Chem 288:2532-45
Morgan, Clinton T; Noble, Daniel; Kimble, Judith (2013) Mitosis-meiosis and sperm-oocyte fate decisions are separable regulatory events. Proc Natl Acad Sci U S A 110:3411-6

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