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

Assistant Professor
Cell & Developmental Biology

Academic Background

Laura Lee received her B.A. in Biochemistry from Rice University and her M.D./Ph.D. degrees from the University of Texas Southwestern Medical School in Dallas, where she performed her thesis work with Dr. Sandra Hofmann. She performed her postdoctoral training with Dr. Gerald Rubin (University of California, Berkeley) and with Dr. Terry Orr-Weaver (The Whitehead Institute). She became an Assistant Professor in the Department of Cell & Developmental Biology at Vanderbilt University Medical School in the fall of 2003. She is a recipient of a Basil O'Connor Starter Scholar Research Award from the March of Dimes Foundation.

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 (e.g. ~70% of genes known to be associated with human diseases are conserved in Drosophila) combined with the superb genetics and cell biology of Drosophila make it an attractive model organism for studying the cell cycle.

DNA staining of wild type (top) and cell-cycle mutant (bottom) embryos reveals cell-cycle arrest with severe polyploidy during the syncytial cycles of early embryogenesis.

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 in the early embryo. Embryos from null mcph1 females undergo a mitotic arrest that appears to be a consequence of mitotic entry in the face of DNA defects. In collaboration with Dr. Scott Waddell's lab (U Mass, Worcester), we have found that brains of mcph1 adult male flies have defects in mushroom body structure, suggesting an evolutionarily conserved role for MCPH1 in brain development. Current efforts are directed towards identifying the molecular pathways in which MCPH1 participates by using both Drosophila genetics and biochemical approaches.

nopo encodes a candidate E3 ubiquitin ligase that controls the 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 a mitotic arrest that appears to be 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"), multipolar spindles, and misaligned chromosomes. We have identified the nopo gene as the homolog of a human gene encoding TRAF-Interacting Protein (TRIP), which has been implicated in TNF signaling. The NOPO protein contains a RING domain and is a candidate E3 ubiquitin ligase. A more detailed phenotypic analysis of nopo mutants is currently underway.

Mat89Bb is required for spermatogenesis
We previously identified Mat89Bb as a substrate of PNG, a kinase that plays a critical role in coordinating DNA replication and mitosis in the early embryo of Drosophila. We have been characterizing a loss-of-function allele of Mat89Bb. Unexpectedly, we have found that Mat89Bb is required for male fertility. We observe defects in physical coupling between the nucleus and centrosomes throughout spermatogenesis in Mat89Bb males. Current efforts are directed towards understanding the molecular basis for these defects.

Rotation projects