This project seeks to gain an understanding of the fundamental process of animal cell cleavage (cytokinesis). It has recently become apparent that animal cell cytokinesis is executed in two phases: the ingression of a circumferential cleavage furrow and the final breaking and resealing of membrane at the residual intercellular bridge (scission). The investigations will focus on the mechanisms that are used to execute scission in the early development of the nematode Caenorhabditis elegans. Prevoius studies have shown that the process of scission requires the presence of the mid-body of the mitotic spindle and targetedocytosis in the region of the cleavage furrow. It is proposed to use functional suppression of genes that encode components of the mid-body coupled with cytological examination of the resultant phenotype in vivo as a means of identifying the role of these components in the machinery that executes scission. We are focusing on two genes that have critical roles in scission, spd-1 and Y18D10A. 17. We will determine how these genes interact with known components of the scission machinery and will also seek other interacting proteins in order to uncover the genetic pathways used in scission. These studies will be complemented by studies of membrane trafficking to the region of the intercellular bridge at the time of scission. Through the use of compartment-specific probes used in conjunction with in vivo imaging, the source of the membrane that is targeted to the late cleavage furrow during scission will be determined. The in vivo observations of the late cytokinetic furrow using the light microscope will be complemented by studies using electron microscopy in order to visualize the ultrastructural interrelationship between the cytoskeletal components of the mid-body and membrane traffic. Cytokinesis is a fundamental cellular process, and as such its malfunction could result in pathologies. If a cleavage fails, any subsequent cleavage of the resulting multipolar cell would result in anuploid daughter cells, which could lose normal growth controls and proliferate inappropriately. For example, filaments of asbestos as are known to interfere with cleavage furrows. This mechanism could explain the carcinagenetic effects of asbestos exposure.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Deatherage, James F
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University of Wisconsin Madison
Other Domestic Higher Education
United States
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Bembenek, Joshua N; Richie, Christopher T; Squirrell, Jayne M et al. (2007) Cortical granule exocytosis in C. elegans is regulated by cell cycle components including separase. Development 134:3837-48
Poteryaev, Dmitry; Squirrell, Jayne M; Campbell, Jay M et al. (2005) Involvement of the actin cytoskeleton and homotypic membrane fusion in ER dynamics in Caenorhabditis elegans. Mol Biol Cell 16:2139-53
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Siomos, M F; Badrinath, A; Pasierbek, P et al. (2001) Separase is required for chromosome segregation during meiosis I in Caenorhabditis elegans. Curr Biol 11:1825-35