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.
- 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) - 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) - 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) - 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) - 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) - 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) - 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) - 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) - 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) - 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)