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Michael McKeown |
Research Summary
My lab is interested in the way genes interact to control interesting processes in complex organisms. We use the non-pathogenic fruit fly Drosophila melanogaster as a model system that is complex enough to be interesting and simple enough to be genetically and experimentally tractable. In addition, a substantial fraction of critical genes and proteins are conserved between Drosophila and vertebrates. Of particular interest at the moment is dissection of the genetic, molecular and neural bases of behavior, with sexual behavior serving as a model. An unexpected but exciting spin off from this work has been the identification of a genes involved in age-dependent behavioral and neural degeneration.
Sexual behavior in Drosophila involves stereotypic behaviors in both sexes. A screen based on alterations in an easily scored female behavior has yielded a number of potentially interesting loci, with two genes being substantially characterized. Mutations in both of these effect both sexes, altering sex-specific behavior and sex-specific neural development. Both genes encode DNA binding transcriptional regulators with limited patterns of expression within the brain and CNS at the time when sex-specific behaviors are established. The encoded proteins have a high degree of similarity to some human proteins, although it has not been shown that they are functional homologs. The consequences of loss of expression, or inappropriate gain of expression, of either of these genes on the development of individual neurons is in progress. The regulatory regions of these genes, and alterations within their proteins are currently being used to dissect the nature and function of the sex-specific nervous system.
As part of the studies on sexual behavior, two genes were identified that give rise to age-dependent behavioral or neural degeneration. Mutations in one of these loci lead to early death accompanied by massive apoptotic cell death in the brain. The encoded protein has a novel and previously uncharacterized human homolog. Mutations in the other gene do not shorten life span under optimal laboratory conditions but lead to alterations in sexual and non-sexual behaviors as well as general loss of mobility and control of body carriage. Although the brains of these animals appear grossly normal, the structural integrity of the brain appears to be diminished. Candidate loci for genetic interaction with this gene have been identified, as have related human genes.
Some Recent Publications
Finley, K.D., Taylor, B.J., Milstein, M. and McKeown, M. (1997) dissatisfaction, a gene involved in sex-specific behavior and neural development of Drosophila melanogaster. Proc. Natl. Acad. Sci. 94, 913-918.
Zelhof, A.C., Ghbeish, N., Tsai, C., Evans, R.M., and McKeown, M. (1997) A role for Ultraspiracle, the Drosophila RXR, in morphogenetic furrow movement and photoreceptor cluster formation. Development 124, 2499-2506.
Brunel CA, Madigan SJ, Cassill JA, Edeen PT, McKeown M (1998) pcdr, a novel gene with sexually dimorphic expression in the pigment cells of the Drosophila eye. Dev Genes Evol 208,327-335.
Finley, K.D., Edeen, P.T., Foss, M., Gross, E., Ghbeish, N., Palmer. R.H., Taylor, B.J. and McKeown, M. (1998) dissatisfaction Encodes a Tailless-like Nuclear Receptor Expressed in a Subset of CNS neurons Controlling Drosophila Sexual Behavior. Neuron 21, 1363-1374.
Scully, A.L., McKeown, M., and Thomas, J.B. (1999) Isolation and characterization of Dek, A Drosophila Eph protein tyrosine kinase. Mol. Cell. Neurosci. 13, 337-347.
Palmer, R. H., Fessler, L. I., Edeen, P. T., Madigan, S. J., McKeown, M., and Hunter, T. (1999) DFak56 is a novel Drosophila melanogaster focal adhesion kinase.. J. Biol. Chem. 274, 35621-35629.
Tsai, C.-C., Kao, H.-Y., Yao, T.-P., McKeown, M., and Evans, R.M. (1999)
SMRTER, a Drosophila nuclear receptor co-regulator, reveals that EcR mediated
repression is critical for development. Molecular
Cell. 4, 175-186.
Brunel, C., Ehresmann, B., Ehresmann, C., and McKeown, M. (2001) Selection
of Genomic Target RNAs by Iterative Screening. Bioorganic and Medical Chemistry.
9/10, 2533-2541.
Ghbeish, N., Tsai, C.-C., Schubiger, M., Zhou, J.Y., Evans, R.M. and McKeown,
M. (2001) The dual role of Ultraspiracle, the Drosophila RXR, in the ecdysone
response. Proc. Natl.
Acad. Sci, USA. 98, 3867-3872.
Lorén, C.E., Scully, A., Grabbe, C., Edeen, P.T., Thomas, J., McKeown,
M., Hunter, T. and Palmer, R.H. (2001) Identification and characterization
of DAlk: a novel Droophila melanogaster RTK which drives ERK activation in
vivo. Genes
to Cells 6, 531-544.
Ghbeish, N. and McKeown, M. (2002) Analyzing the repressive function of Ultraspiracle,
the Drosophila RXR, in Drosophila eye development. Mech
Dev 111, 89-98.
Pitman, J.L., Tsai, C.-C., Edeen, P.T., Finley, K.D., Evans, R.M. and McKeown,
M. (2002) DSF nuclear receptor acts as a repressor in culture and in vivo.
Dev
Biology 245, 315-328.
Finley, K.D., Edeen, P.T., Cumming, R.C., Mardahl-Dumesnil, M.D., Taylor, B.J., Rodriguez, M.H., Hwang, C.E., Benedetti, M, and McKeown, M. (2003) Blue cheese mutations define a novel, conserved gene involved in progressive neural degradation. J. Neuroscience 23, 1254-1264.
Faculty Listing | Program in Biology | School of Medicine | MCB Grad Program