The long-term objective of this proposal is the elucidation of the cellular, genetic and molecular mechanisms that control patterns of cell division and cell fate during development. Toward this end, genes involved in specific aspects of the development of the nematode Caenorhabditis elegans will be identified and characterized. Particular emphasis will be placed on the genetic analysis of the cell-cell interactions that control the cell lineages of C. elegans vulval development. The genetic pathway of vulval development is the most extensively defined pathway in C. elegans. New genes in this pathway will be sought by identifying mutations that result in novel classes of vulval abnormalities as well as mutations that either suppress or enhance the phenotypes caused by existing vulval developmental mutations. Certain non-vulval cell lineages also will be studied. To elucidate the nature and specificity of the action of particular genes that affect cell lineages, detailed genetic analyses will be performed. For example, both how existing mutations perturb gene activity and the """"""""null"""""""" (loss-of-function) phenotype of each gene will be determined. In addition, temperature-shift experiments will reveal the time(s) of gene action, and mosaic analyses will reveal the site(s) of gene action. Gene interactions will be analyzed to define genetic pathways. Genes that perturb programmed cell deaths also will be examined; both genes that affect the """"""""program"""""""" of programmed cell death and genes that specify which cells are to express this program will be sought and characterizes. Genes that control cell lineage and cell fate will be molecularly cloned and analyzed; these experiments should define developmental pathways at a molecular level and may elucidate the molecular bases of the specification of cell lineage and cell fate. The study of C. elegans cell lineage should reveal how cell division is normally controlled in a multicellular animal and how this control can be disrupted. Such knowledge may prove relevant to an understanding of the cellular proliferation that characterized cancerous growth. Knowledge of the mechanisms of programmed cell death and the ways in which mutations can perturb patterns of cell death may indicate the bases of human disorders involving abnormal cell deaths. In addition, a basic understanding of nematode biology should help in the prevention and treatment of diseases caused by parasitic nematodes, which are a major source of human suffering in the world today.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM024943-10
Application #
3272671
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1978-04-01
Project End
1991-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
10
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Galvin, Brendan D; Kim, Saechin; Horvitz, H Robert (2008) Caenorhabditis elegans genes required for the engulfment of apoptotic corpses function in the cytotoxic cell deaths induced by mutations in lin-24 and lin-33. Genetics 179:403-17
Horvitz, H R (1999) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res 59:1701s-1706s
Herman, M A; Vassilieva, L L; Horvitz, H R et al. (1995) The C. elegans gene lin-44, which controls the polarity of certain asymmetric cell divisions, encodes a Wnt protein and acts cell nonautonomously. Cell 83:101-10
Labouesse, M; Sookhareea, S; Horvitz, H R (1994) The Caenorhabditis elegans gene lin-26 is required to specify the fates of hypodermal cells and encodes a presumptive zinc-finger transcription factor. Development 120:2359-68
Horvitz, H R; Shaham, S; Hengartner, M O (1994) The genetics of programmed cell death in the nematode Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol 59:377-85
Clark, S G; Lu, X; Horvitz, H R (1994) The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins. Genetics 137:987-97
Avery, L; Bargmann, C I; Horvitz, H R (1993) The Caenorhabditis elegans unc-31 gene affects multiple nervous system-controlled functions. Genetics 134:455-64
Clark, S G; Chisholm, A D; Horvitz, H R (1993) Control of cell fates in the central body region of C. elegans by the homeobox gene lin-39. Cell 74:43-55
Yuan, J; Horvitz, H R (1992) The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116:309-20
Clark, S G; Stern, M J; Horvitz, H R (1992) Genes involved in two Caenorhabditis elegans cell-signaling pathways. Cold Spring Harb Symp Quant Biol 57:363-73

Showing the most recent 10 out of 37 publications