• Centrosome function in cell division and development
Centrosomes coordinate the organization of dynamic microtubules to achieve many essential cellular functions. In interphase cells, microtubules establish polarity, migration, intracellular trafficking, and cell shape. At mitosis, centrosomes play a dominant role in organization and assembly of the bipolar spindle apparatus. Accurate assembly of the spindle is essential for proper segregation of the chromosomes at each cell division. In addition, spindle astral microtubules are key to anchoring and orienting the mitotic spindle during polarized cell division, a central tenet of stem cell function. The replication of centrosomes is a highly regulated yet poorly understood process. In G1 phase, a single centrosome contains a pair of centrioles: a mature mother centriole and its daughter. Most animal cells, upon differentiation or entry into G0, contain a single primary cilium whose assembly is templated by the mother centriole, which is referred to as a basal body when it is engaged in cilium formation. With the emergence of the cilium as a key appendage for cell signaling and animal development, interest in this organelle has experienced a renaissance. Moreover, there is an ever-expanding list of disease syndromes that are linked to dysfunction of centrosomes, basal bodies, and cilia.
The structure of the centrosome and the proteins that comprise it are only recently becoming elucidated. The identification of centrosomal factors is underway in the lab in conjunction with functional studies in vivo and in cultured cells using genetic, imaging and biochemical approaches in flies and mouse.
-- Centrosomin and CDK5RAP2 --
Centrosomin (Cnn), originally identified by our work in flies, has family members from yeast to humans. In humans, mutations in one of the two orthologs, CDK5RAP2, causes autosomal recessive primary microcephaly (MCPH), a developmental syndrome in which individuals develop a severely reduced cerebral cortex. We have developed Drosophila and mouse models for Cnn and CDK5RAP2 function to dissect the functions of these essential centrosome proteins.
Cnn and Cdk5rap2 are required for microtubule assembly at centrosomes, for signaling actin assembly into cleavage furrows and for regulating the control of centriole replication. We have defined the determinants involved in these activities including the identification of the key interacting partners that cooperate with Cnn and Cdk5rap2 to control these functions. Future efforts will define the pathways that these centrosome proteins disrupt in cell division, development and disease.
• Tumor virus pathogenesis in Drosophila
Viruses like high-risk human papillomavirus (HPV) hijack the cell?s biochemistry to promote viral replication through the activation of cell division and the inhibition of apoptosis. HPV is the major cause of cervical cancer, responsible for 99.4% of incidences. We have developed Drosophila expression models for the tumor antigens involved in tumorigenesis by HPV-16, Simian Virus 40 (SV40) and Adenovirus-5. Initial efforts have validated the modeling of these viral proteins pathologies in Drosophila for human disease pathogenesis, and revealed novel activities for these oncoproteins. Ongoing efforts will define the pathways these proteins use to impact cell, development, and disease progression.
RESEARCH INTERESTS
Centrosome
Cytoskeleton
Mitosis
stem cells
cilia
RECENT PUBLICATIONS
Kao LR, and Megraw TL, "Centrocortin cooperates with Centrosomin to Organize Drosophila Cleavage Furrows" Curr Biol, in press 2009
Mottier-Pavie V and Megraw, TL, "Drosophila Bld10 is a Centriolar Protein that Regulates Centriole, Basal Body, and Motile Cilium Assembly." Mol Biol Cell., 2009
Kotadia, S., Kao, L.R., Comerford, S.A., Jones, R.T., Hammer, R.E. and T.L. Megraw., "PP2A-dependent disruption of centrosome replication and cytoskeleton organization in Drosophila by SV40 small tumor antigen." Oncogene, 27:6334-46, November 2008
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, 18:4037-49, September 2007
Megraw TL, Kao LR, Kaufman TC, "Zygotic development without functional mitotic centrosomes" Curr Biol, 11(2):116-120, January 2001
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