Profile

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

The following timeline graph is generated from all co-authored publications.

  1. Human Asunder promotes dynein recruitment and centrosomal tethering to the nucleus at mitotic entry. Jodoin JN, Shboul M, Sitaram P, Zein-Sabatto H, Reversade B, Lee E, Lee LA (2012) Mol Biol Cell 23(24): 4713-24
    › Primary publication · 23097494 (PubMed) · PMC3521680 (PubMed Central)
  2. Regulation of dynein localization and centrosome positioning by Lis-1 and asunder during Drosophila spermatogenesis. Sitaram P, Anderson MA, Jodoin JN, Lee E, Lee LA (2012) Development 139(16): 2945-54
    › Primary publication · 22764052 (PubMed) · PMC3403104 (PubMed Central)
  3. XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Hanson AJ, Wallace HA, Freeman TJ, Beauchamp RD, Lee LA, Lee E (2012) Mol Cell 45(5): 619-28
    › Primary publication · 22304967 (PubMed) · PMC3299836 (PubMed Central)
  4. Screening for small molecule inhibitors of embryonic pathways: sometimes you gotta crack a few eggs. Hang BI, Thorne CA, Robbins DJ, Huppert SS, Lee LA, Lee E (2012) Bioorg Med Chem 20(6): 1869-77
    › Primary publication · 22261025 (PubMed) · PMC3298638 (PubMed Central)
  5. A biochemical screen for identification of small-molecule regulators of the Wnt pathway using Xenopus egg extracts. Thorne CA, Lafleur B, Lewis M, Hanson AJ, Jernigan KK, Weaver DC, Huppert KA, Chen TW, Wichaidit C, Cselenyi CS, Tahinci E, Meyers KC, Waskow E, Orton D, Salic A, Lee LA, Robbins DJ, Huppert SS, Lee E (2011) J Biomol Screen 16(9): 995-1006
    › Primary publication · 21859680 (PubMed) · PMC3694444 (PubMed Central)
  6. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, Jernigan KK, Meyers KC, Hang BI, Waterson AG, Kim K, Melancon B, Ghidu VP, Sulikowski GA, LaFleur B, Salic A, Lee LA, Miller DM, Lee E (2010) Nat Chem Biol 6(11): 829-36
    › Primary publication · 20890287 (PubMed) · PMC3681608 (PubMed Central)
  7. Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity. Jernigan KK, Cselenyi CS, Thorne CA, Hanson AJ, Tahinci E, Hajicek N, Oldham WM, Lee LA, Hamm HE, Hepler JR, Kozasa T, Linder ME, Lee E (2010) Sci Signal 3(121): ra37
    › Primary publication · 20460648 (PubMed) · PMC3088111 (PubMed Central)
  8. Asunder is a critical regulator of dynein-dynactin localization during Drosophila spermatogenesis. Anderson MA, Jodoin JN, Lee E, Hales KG, Hays TS, Lee LA (2009) Mol Biol Cell 20(11): 2709-21
    › Primary publication · 19357193 (PubMed) · PMC2688550 (PubMed Central)
  9. no poles encodes a predicted E3 ubiquitin ligase required for early embryonic development of Drosophila. Merkle JA, Rickmyre JL, Garg A, Loggins EB, Jodoin JN, Lee E, Wu LP, Lee LA (2009) Development 136(3): 449-59
    › Primary publication · 19141674 (PubMed) · PMC2687590 (PubMed Central)
  10. alpha-Endosulfine is a conserved protein required for oocyte meiotic maturation in Drosophila. Von Stetina JR, Tranguch S, Dey SK, Lee LA, Cha B, Drummond-Barbosa D (2008) Development 135(22): 3697-706
    › Primary publication · 18927152 (PubMed) · PMC2654389 (PubMed Central)