Proper control of the cell cycle is essential for the formation and survival of multi-cellular organisms. Derangements in cell-cycle regulation are often observed in pathological states such as cancer and birth defects. The Laura Lee lab uses Drosophila melanogaster (the simple fruit fly) to study cell-cycle regulation during the development of a multi-cellular organism. The superb genetics and cell biology of Drosophila combined with the high degree of functional conservation of genes make it an attractive model organism. Drosophila genetics is the major tool that the lab uses to identify and characterize genes that regulate the cell cycle. Lab members complement genetic approaches with cell biology and biochemistry, including genome-scale biochemical screening. They also use cultured mammalian cells and Xenopus embryos (in collaboration with the Ethan Lee lab) to further characterize genes identified in Drosophila that play conserved cell-cycle roles in higher organisms.

One focus of the Laura Lee lab is the maintenance of genomic stability during early embryogenesis. They have identified no poles (nopo) in a genetic screen for cell-cycle regulators in the early embryo. Embryos from null nopo females undergo mitotic arrest with spindles that lack centrosomes (hence the name "no poles") and misaligned chromosomes; we have found that this arrest is secondary to activation of a DNA checkpoint. The predicted NOPO protein contains a RING domain and is a candidate E3 ubiquitin ligase. The human homolog of nopo encodes TRAF-Interacting Protein (TRIP), which has been implicated in TNF signaling. Current efforts are directed towards identifying NOPO targets using both genetic and biochemical approaches.

A second focus of the lab is the regulation of spermatogenesis. The lab's mutational analysis has revealed that asunder (asun), which encodes a conserved protein, is required during Drosophila spermatogenesis. Spermatocytes in asun testes arrest during prophase of meiosis I with free centrosomes that fail to stably associate with the nucleus. They have renamed this gene asunder (asun; previously known as Mat89Bb based on its maternal expression) to reflect its loss-of-function phenotype. asun spermatocytes that evade arrest exhibit severe defects in meiotic spindle assembly, chromosome segregation, and cytokinesis. The basal body fails to stably associate with the nucleus in post-meiotic asun spermatids, resulting in further defects in late spermatogenesis. The lab's data indicate that all of these defects are due to a lack of proper localization of dynein, a microtubule motor, to the nuclear surface in asun spermatocytes. Current efforts are directed towards understanding the basis for regulation of dynein by asun.

NEWEST PUBLICATIONS

A biochemical screen for identification of small-molecule regulators of the Wnt pathway using Xenopus egg extracts.
2011 Journal of Biomolecular Screening 16: 995-1006

Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
2010 Nature Chemical Biology 6: 829-836

PREVIOUS PUBLICATIONS

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