The long term goal of this work is to understand how cell division and differentiation are regulated in response to a combination of extracellular and intracellular signals. In humans improper control of cell division and/or differentiation may produce a variety of developmental abnormalities, including birth defects, cancer and autoimmune disease. The specific focus of this research is geared toward understanding how cell division and differentiation are regulated within the germline of the nematode, Caenorhabditis elegans. In the adult germline, mitoses are confined to the distal region of the gonad; germ cells that have progressed proximally from this region enter meiosis and initiate gametogenesis. Previous work has demonstrated that meiotic progression (specifically exit from pachytene) is dependent on several genes of the MAP kinase cascade (let-60 RAS, lin-45 RAF, mek-2 MAPKK and mpk-1 MAPK), each of which is also required for the induction of the hermaphrodite vulva. More recent data suggest that RAS-MAPK may also regulate distal proliferation and apoptosis within the germline.One of the goals of the work proposed here is to characterize a newly identified gene, pex-1 (pachytene exit), which is required for exit from pachytene, but not for vulval induction. Other mutations that specifically affect exit from pachytene will also be sought and characterized. In addition, a combination of genetic, molecular and cell biological methods will be directed toward determining how RAS is activated in the germline and identifying the targets of MAPK in the germline. Reverse genetic methods will be used to determine whether the regulation of pachytene exit within the nematode germline utilizes gene products homologous to those that control oocyte maturation in vertebrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM049785-04A1
Application #
2022758
Study Section
Genetics Study Section (GEN)
Project Start
1993-08-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Lambie, Eric J; Bruce 3rd, Robert D; Zielich, Jeffrey et al. (2015) Novel Alleles of gon-2, a C. elegans Ortholog of Mammalian TRPM6 and TRPM7, Obtained by Genetic Reversion Screens. PLoS One 10:e0143445
Lee, Min-Ho; Ohmachi, Mitsue; Arur, Swathi et al. (2007) Multiple functions and dynamic activation of MPK-1 extracellular signal-regulated kinase signaling in Caenorhabditis elegans germline development. Genetics 177:2039-62
Kemp, Benedict J; Hatzold, Julia; Sternick, Laura A et al. (2007) In vivo construction of recombinant molecules within the Caenorhabditis elegans germ line using short regions of terminal homology. Nucleic Acids Res 35:e133
Chen, Carlos Chih-Hsiung; Schweinsberg, Peter J; Vashist, Shilpa et al. (2006) RAB-10 is required for endocytic recycling in the Caenorhabditis elegans intestine. Mol Biol Cell 17:1286-97
Teramoto, Takayuki; Lambie, Eric J; Iwasaki, Kouichi (2005) Differential regulation of TRPM channels governs electrolyte homeostasis in the C. elegans intestine. Cell Metab 1:343-54
Church, Diane L; Lambie, Eric J (2003) The promotion of gonadal cell divisions by the Caenorhabditis elegans TRPM cation channel GON-2 is antagonized by GEM-4 copine. Genetics 165:563-74
Lambie, Eric J (2002) Cell proliferation and growth in C. elegans. Bioessays 24:38-53
West, R J; Sun, A Y; Church, D L et al. (2001) The C. elegans gon-2 gene encodes a putative TRP cation channel protein required for mitotic cell cycle progression. Gene 266:103-10
Sun, A Y; Lambie, E J (1997) gon-2, a gene required for gonadogenesis in Caenorhabditis elegans. Genetics 147:1077-89
Church, D L; Guan, K L; Lambie, E J (1995) Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans. Development 121:2525-35