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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 

Laura A. Lee, M.D., Ph.D.

Associate Professor of Cell and Development Biology
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
1161 21st Ave, U-4227 Learned Lab
Nashville, TN 37232-2175
615-322-1331
Fax: 615-343-4539

Research Description

RESEARCH INTERESTS

Proper control of the cell cycle is essential for the formation and survival of multi-cellular organisms, and derangements in cell-cycle regulation are often observed in pathological states such as cancer and birth defects. My laboratory uses Drosophila melanogaster to study cell-cycle regulation during the development of a multi-cellular organism. The high degree of functional conservation of genes combined with the superb genetics and cell biology of Drosophila make it an attractive model organism.

EXPERIMENTAL APPROACHES

Drosophila genetics is the major tool we use to identify and characterize new genes that regulate the cell cycle. We complement our genetic approaches with both cell biology and biochemistry, including genome-scale biochemical screening. We also utilize cultured mammalian cells and Xenopus embryos (in collaboration with Dr. Ethan Lee) to further characterize new genes identified in Drosophila that play conserved roles in cell-cycle regulation in higher organisms.

CELL CYCLE REGULATION BY DROSOPHILA MCPH1

Mutations in the human microcephalin (MCPH1) gene result in primary microcephaly ("small head" in Greek), a developmental condition in which cerebral cortex size is severely reduced. We identified mcph1, the Drosophila homolog of human MCPH1, in a genetic screen for cell-cycle regulators. Embryos from null mcph1 females undergo mitotic arrest as a consequence of mitotic entry in the face of DNA defects. Current efforts are directed towards identifying the pathways in which MCPH1 participates by using both genetic and biochemical approaches.

NOPO IS A CANDIDATE E3 UBIQUITIN LIGASE THAT CONTROLS EARLY EMBRYONIC CELL CYCLE

We also identified no poles (nopo) in our genetic screen for cell-cycle regulators in the early embryo. Like mcph1, embryos from null nopo females undergo mitotic arrest secondary to mitotic entry with damaged or incompletely replicated DNA. nopo-derived embryos exhibit a high frequency of spindles that lack centrosomes (hence the name "no poles") and misaligned chromosomes. The predicted NOPO protein contains a RING domain and is a candidate E3 ubiquitin ligase. Current efforts are directed towards identifying NOPO targets using both genetic and biochemical approaches.

MAT89Bb IS REQUIRED FOR SPERMATOGENESIS

We identified Mat89Bb as a substrate of PNG, a kinase that coordinates cell cycles in early embryos of Drosophila. Unexpectedly, we have found by mutant analysis that Mat89Bb is required for male fertility. We observe defects in coupling between the nucleus and centrosomes throughout spermatogenesis in Mat89Bb males leading to defects in meiotic spindle assembly and chromosome segregation. Our data indicate that these defects are due to lack of proper localization of dynein, a microtubule motor, to the nuclear periphery in Mat89Bb spermatocytes. Current efforts are directed towards understanding the basis for regulation of dynein by Mat89Bb.

Publications