• Centrosome function in cell division and development
Productive cell division depends upon the accurate segregation of chromosomes at mitosis. The regulation and orchestration of this process is critical during growth and development, and its failure can lead to chromosome instability, resulting in cell death or oncogenesis. Key to this process, the accurate assembly of the bipolar spindle apparatus ensures that the cytoskeletal machinery necessary to accomplish this task is in place. In most animal cells, the centrosome is the primary microtubule-organizing center (MTOC). The structure of the centrosome and the proteins that comprise it are only recently becoming elucidated. The identification of centrosomal factors is underway in conjunction with functional studies in vivo and in cultured cells using genetic and biochemical approaches.
In the absence of functional centrosomes, cells can assembly a mitotic spindle via an alternate, chromosome-driven pathway. We have modeled this pathway in the fruit fly Drosophila melanogaster, and genetic methods are being employed to dissect the components required for centrosome and centrosome-free pathways of cell division. Stem cells, which divide asymmetrically, have a unique requirement for centrosomes to accomplish polarized mitosis. For example, neurogenesis relies upon controlled spindle rotation during stem cell divisions to ensure accurate cell fate determinations upon cell division. A mouse model has been developed in our lab, providing a unique opportunity to investigate these centrosome functions during mammalian development.
• Centriole biogenesis
A pair of centrioles, buried within the pericentriolar matrix, is required for centrosome assembly. Regulation of centriole biogenesis, whether by ?templated duplication? or de novo synthesis, is a tightly regulated process in the cell cycle. Control over centriole duplication is important to restrict centrosome numbers in the cell, since too many (more than two) centrosomes can result in chromosome segregation errors at cell division. One recognized hallmark of progressed cancer cells is amplification of centrosome numbers, having a causative affect on chromosomal instability.
Mutations in centriole proteins in flies and mice are being used to understand how centriole biogenesis is controlled. In addition, we are employing expression of viral oncoproteins in Drosophila as tools to dissect the pathways that normally govern control over centriole numbers. In the course of this analysis, we have established Drosophila as a model to understand pathologies associated with DNA tumor viruses (HPV, Adenovirus and SV40).
RESEARCH INTERESTS
Centrosome
Cytoskeleton
Mitosis
stem cells
cell cycle
RECENT PUBLICATIONS
Zhang, J and Megraw, TL, "Proper Recruitment of γ-Tubulin and D-TACC/Msps to Embryonic Drosophila Centrosomes Requires Centrosomin Motif 1" Molecular Biology of the Cell, in press September 2007
Kao, LR and Megraw, TL, "RNAi in cultured Drosophila cells." Methods Mol Biol., 247:443-57, 2004
Megraw TL, Kilaru S, Turner FR, Kaufman TC., "The centrosome is a dynamic structure that ejects PCM flares" J. Cell Sci, 115:4707-4718, December 2002
Megraw TL, Kao LR, Kaufman TC, "Zygotic development without functional mitotic centrosomes" Curr Biol, 11(2):116-120, January 2001
Megraw TL, Kaufman TC., "The centrosome in Drosophila oocyte development" Curr Top Dev Biol, 49:385-407, 2000
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