 |
|
|
Timothy Megraw Ph.D.
|
|
Associate Professor
|
|
timothy.megraw@med.fsu.edu
|
|
850-645-9271
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Education |
Postdoc, Molecular Genetics, Indiana University and the Howard Hughes Medical Institute
PhD, Biochemistry, The University of North Carolina at Chapel Hill
BS, Biochemistry, The State University of New York at Stony Brook
|
|
|
|
|
|
|
|
|
Memberships
|
American Society for Cell Biology
Genetics Society of America
|
|
Research Focus
|
--To see lab web page click HERE--
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 constitute it are only recently becoming elucidated. The identification of centrosomal factors is under way in the lab in conjunction with functional studies in vivo and in cultured cells using genetic, imaging and biochemical approaches in flies and mice.
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.
|
Publications
|
|
Zhang, J. and T.L. Megraw. Motif 1 of Centrosomin recruits g-Tubulin and D-TACC/Msps to embryonic Drosophila centrosomes. Mol Biol Cell, 18, 4037-49 (2007). PMC1995719
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(49): p. 6334-46 (2008). PMC2575340
Mottier-Pavie, V. and T.L. Megraw. Drosophila Bld10 is a centriolar protein that regulates centriole, basal body and motile cilium assembly. Mol Biol Cell, 20(10):2605-14 (2009). This paper was featured on the cover. PMC2682601
Kao, L.R. and T.L. Megraw. Centrocortin cooperates with Centrosomin to organize Drosophila embryonic cleavage furrows. Current Biology, 19(11): 937-942 (2009). Special Commentaries: Curr Biol and was recommended by Faculty of 1000
Barrera, J.A., Kao, L.R., Hammer, R.E. and T.L. Megraw. CDK5RAP2 Regulates Centriole Licensing in Mice. Accepted with revision at Dev Cell.
|
|
|
|
|
|
|
