During every cell division, the genome needs to be duplicated accurately and a complete set of chromosomes segregated faithfully to each of the daughter cells. Errors in chromosome segregation can have dramatic consequences, as loss or duplication of chromosomes can lead to cell death, result in birth defects or contribute to cancer. How can accurate segregation of chromosomes be accomplished? How can it fail? To answer these questions we need to understand the molecular basis of the mitotic machinery: what are the components used and how do they act to accomplish centrosome duplication, spindle assembly, chromosome movement, sister chromatid separation and a correct timing of all the steps involved? We use Caenorhabditis elegans as a model system to identify genes involved in chromosome segregation in animal cells. To initiate these studies we have focused on the C. elegans gene lin-5. In lin-5 null mutants, cells enter mitosis but chromosomes do not become aligned at the metaphase plate and anaphase is not initiated. Despite these defects, cells exit from mitosis without delay and initiate subsequent rounds of centrosome duplication and DNA replication followed by abortive mitoses. We have cloned the lin-5 gene and found that it is predicted to encode a novel protein. Importantly, the LIN-5 protein localizes to the centrosomes during mitosis. This proposal details our experiments aimed at further understanding the function of lin-5 in vivo. i) we will obtain a precise characterization of the lin-5 mutant phenotype at the cellular level and determine its relationship to the functions of other genes with roles in mitosis (Specific aim 1). ii) We will use genetic approaches to define genes that act in the same mitotic process as lin-5 and characterize those that are the most interesting at a molecular level. As candidates, we have recently isolated an extensive number of mutants that enhance or suppress a temperature-sensitive lin-5 allele (Specific Aims 2 and 3). These studies aim to take advantage of C. elegans as an animal model in which genetics can be used to study cell-cycle regulation during development. Our goals are 1) to determine the function of the lin-5 gene, 2) to identify novel components of the mitotic machinery and 3) to understand how they work together with known components to regulate chromosome segregation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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Zatz, Marion M
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Massachusetts General Hospital
United States
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van der Voet, Monique; Lorson, Monique A; Srinivasan, Dayalan G et al. (2009) C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation. Cell Cycle 8:4091-102
van der Voet, Monique; Berends, Christian W H; Perreault, Audrey et al. (2009) NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Galpha. Nat Cell Biol 11:269-77
Saito, R Mako; van den Heuvel, Sander (2002) Malignant worms: what cancer research can learn from C. elegans. Cancer Invest 20:264-75