The broad goal of this work is to understand the genetic and molecular mechanisms of the temporal control of cell division and differentiation using the nematode C. elegans as a model. Genetic and molecular analysis will be performed to determine how the regulatory pathway of heterochronic genes controls the temporally coordinated expression of diverse developmental events in C. elegans larvae. Emphasis will be placed on understanding how certain general temporal control genes specify the timing of events in diverse cell types and how other genes respond to these regulators to execute particular developmental and cell cycle programs. Genetic screens will be employed to identify new genes in this pathway. Key genes will be analyzed molecularly to determine the structure and expression of their products, and how they interact with the products of other heterochronic genes. Mosaic analysis will be used to assess the role of these genes in cell-cell signaling processes that coordinate developmental programs in separate cell lineages. Emphasis will be placed on understanding the molecular mechanism of how lin-14 and lin-28, genes that play central roles in the control of understanding the molecular mechanism of how lin-14 and lin-28, genes that play central roles in the control of diverse larval cell lineages., are regulated by the novel regulatory molecule encoded by lin-4. Also, a major effort will be focused on understanding how the heterochronic genes control cell cycle and developmental competence of vulval precursor cells. Generally speaking, the C. elegans heterochronic genes offer an opportunity to study the genetic and molecular mechanisms controlling cell division and differentiation, processes central to all multi-cellular development. More specifically, the fact that the heterochronic genes affect developmental timing provides a unique system in which to examine in detail the regulatory mechanisms underlying temporal control.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034028-19
Application #
6525867
Study Section
Genetics Study Section (GEN)
Program Officer
Greenberg, Judith H
Project Start
1984-07-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
19
Fiscal Year
2002
Total Cost
$397,500
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
McJunkin, Katherine; Ambros, Victor (2017) A microRNA family exerts maternal control on sex determination in C. elegans. Genes Dev 31:422-437
Ren, Zhiji; Veksler-Lublinsky, Isana; Morrissey, David et al. (2016) Staufen Negatively Modulates MicroRNA Activity in Caenorhabditis elegans. G3 (Bethesda) 6:1227-37
Burke, Samantha L; Hammell, Molly; Ambros, Victor (2015) Robust Distal Tip Cell Pathfinding in the Face of Temperature Stress Is Ensured by Two Conserved microRNAS in Caenorhabditis elegans. Genetics 200:1201-18
Ren, Zhiji; Ambros, Victor R (2015) Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress. Proc Natl Acad Sci U S A 112:E2366-75
Sterling, Catherine H; Veksler-Lublinsky, Isana; Ambros, Victor (2015) An efficient and sensitive method for preparing cDNA libraries from scarce biological samples. Nucleic Acids Res 43:e1
Zinovyeva, Anna Y; Veksler-Lublinsky, Isana; Vashisht, Ajay A et al. (2015) Caenorhabditis elegans ALG-1 antimorphic mutations uncover functions for Argonaute in microRNA guide strand selection and passenger strand disposal. Proc Natl Acad Sci U S A 112:E5271-80
Harandi, Omid F; Ambros, Victor R (2015) Control of stem cell self-renewal and differentiation by the heterochronic genes and the cellular asymmetry machinery in Caenorhabditis elegans. Proc Natl Acad Sci U S A 112:E287-96
Nelson, Charles; Ambros, Victor; Baehrecke, Eric H (2014) miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell 56:376-88
Zinovyeva, Anna Y; Bouasker, Samir; Simard, Martin J et al. (2014) Mutations in conserved residues of the C. elegans microRNA Argonaute ALG-1 identify separable functions in ALG-1 miRISC loading and target repression. PLoS Genet 10:e1004286
McJunkin, Katherine; Ambros, Victor (2014) The embryonic mir-35 family of microRNAs promotes multiple aspects of fecundity in Caenorhabditis elegans. G3 (Bethesda) 4:1747-54

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