Faculty Profile: Michael McKeown, Ph.D., University of California, San Diego, 1981

Michael McKeown
Michael McKeown, Ph.D., University of California, San Diego, 1981
Professor of Medical Science
Molecular Biology, Cell Biology, & Biochemistry
Work: +1 401-863-9807
My lab is interested in the way genes interact to control interesting processes in complex organisms, with particular emphasis on generation of complex behaviors and neural degeneration. We use the non-pathogenic fruit fly Drosophila melanogaster as a model. Since a major fraction of critical genes, proteins, and developmental and neural mechanisms are conserved between flies and vertebrates, a substantial fraction of our findings are directly or indirectly informative about humans.

Much or our current work focuses on the gene and neural networks controlling sexual behavior and orientation. Since males and females generate sex-specific behaviors, this is a powerful system in which to dissect development of mutually exclusive behaviors.

Biography

I attended public schools in northern California before entering Stanford, where I worked with Phil Hanawalt on nucleoside metabolism in E. coli. As an NSF Fellow, I did my graduate work at the UC, San Diego, studying the actin multigene family of Dictyostelium with Rick Firtel. I began my studies of Drosophila sexual differentiation as a Helen Hay Whitney fellow with Bruce Baker. From there I joined the faculty of the Salk Institute for Biological Studies, where I served as an adjunct faculty member at UCSD and became a Pew Scholar in Biomedical Sciences. In 2000 I came to Brown as a Professor of Medical Science.

My wife, Erica, and I have been married for 28 years. Twins Charles and Rebecca graduated from Stanford and Harvard and now are in law school and linguistics graduate school. Younger son Gene is in college at the Rhode Island School of Design.

Prior to coming to Brown, I was active in K-12 mathematics and science education issues. Erica and I are among the founders of Mathematically Correct, a nationwide math advocacy group. I was active in writing the San Diego Math Standards and in the early stages of writing the California Science Standards.

Institutions

Bu

Research Description

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 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 affect 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.

Grants and Awards

ACADEMIC HONORS
Phi Beta Kappa, Spring 1974
Fox Award, Outstanding Biology Undergraduate, Spring 1975
BS with Distinction and Departmental Honors, Spring 1975
Pew Foundation Scholar in the Biomedical Sciences, July 1986
Elected Salk Institute Academic Council, May, 1989, Re-elected April 1991

FELLOWSHIPS
NSF Predoctoral Fellowship, 1975-1978
NIH Predoctoral Traineeships, 1978-1981
NIH Postdoctoral Trainee, 1981-1982
Helen Hay Whitney Foundation Postdoctoral Fellow, 1982-1985

STUDY SECTIONS, US GRANT REVIEWER
NIH Genetics Study Section, October 1995
NIH MDCN-6 Study Section, June 2003
NIH ZRG1 MDCN-A (03) Study Section, March 2006
NIH ZRG1 MDCN-E (02) (M) Special Emphasis Panel/Scientific Review Group 2007/01 December 2006.
NIH NTRC Study Section June 2007
NSF Proposal review April 2007

Affiliations

None

Funded Research

Current:

• dissatisfaction retained and the Sex Behavior Network
Principal Investigator: Michael McKeown
Agency: National Institutes of Health/Institute of Neurological Disorders and Stroke
Type: Research Grant (R01) Score: 125 Percentile: 3.2
Period: 2-1-08 – 1-31-13
Direct cost per year $218,750 - - Total per year $340,625

Completed

• Control of Drosophila neural development and sexual behavior by the retained gene.
Principal Investigator: Michael B. McKeown.
Agency: National Science Foundation
Type: Research Grant (IBN-0315660)
Period 9-1-03 to 8-31-06

• Nuclear Receptor and Co-Repressor Function in Eye Development
Principal Investigator: Michael B. McKeown
Agency: National Science Foundation
Type: Research Grant (IBN-9874448, Years 01-04) Period: July 1, 1999, to June 30, 2004.

•Control of Sex-Specific Neural Development and Behavior
Principal Investigator: Michael B. McKeown
Agency: National Institute of Mental Health
Type: R01 (MH57460, Years 01-04) Period: September 1, 1997, to April 30, 2003.

Behavioral and Neural Deterioration in Drosophila
Principal Investigator: Michael B. McKeown
Agency: National Institutes of Health, NIA
Type: Research Grant (1 R03 AG19614-01) Period: October 1, 2000-September 29, 2002

Dsf co-activators and co-repressors in behavior
Principal Investigator: Michael McKeown
Agency: NSF
Type: Research Grant
Date: July 2005

Submitted
Systems, Biology and Developmental Birth Defects
Principal Investigator: Micheal McKeown
Agency: National Institute of Health, NICHD
Type: T32 Predoctoral Training Grant – 2 students year 1, 4 thereafter Systems Biology of Development and Birth Defects, Submitted Spring 2008

Teaching Experience

My teaching is largely directed to Genetics and Molecular Biology.

Prior to coming to Brown in 2001, I organized and was the lead instructor for Bi0221 Advanced Genetics from 1991-1999, at the University of California, San Diego. This 6 unit, 1 quarter course was the genetics component of the graduate core curriculum for students in the Biology PhD program.

In San Diego I also participated in the Elementary Institute of Science summer research program. This program provided summer laboratory research opportunities for students of under represented groups, or for instructors who taught at schools with a high proportion of students from under represented groups.

From 2001 until 2004 I taught Bi0154 Molecular Genetics to advanced undergraduates and graduate students. This course was based on reading and analysis of papers from the primary literature as a way to understand the ways we use both genetics and molecular biology to dissect complex biological problems.

Since 2003 I have taught Bi0047 Genetics. This is the main undergraduate genetics course and serves as a key component of a solid biogical or premedical training program. This combines classical and bacterial geneticss with more recent advances in genetic and genomic methods, as well as emphasizing molecular biology and molecular genetics. This course stresses mastery of concepts and skills sufficiently to apply them to solving problems.

I have also served as research mentor to a number of undergraduate (Bi0195/196) and graduate students (Bi0295/296).

In addition, I have taught three graduate seminars: Bi0248 Current Topics in Genetics, on the Molecular Biology of Sex, Bio0248 Current Topics in Genetics, on Epigentics, and Biol2490 on Nuclear Hormone Receptors in Growth, Differentiation and Disease.

Since coming to Brown I have also had two Leadership Alliance summer students and a number of other students for summer opportunities as well.

Courses Taught

  • Genetics (Bi0047)
  • Seminar in Genetics (Bi0248)

Selected Publications

  • Wang, L., Rajan, H., Pitman, J.L., McKeown, M., Tsai, C.C. (2006) Histone deacetylase-associating Atrophin proteins are nuclear receptor corepressors. Genes Dev. 20:525-530. (2006)
  • Shirangi, TR, Taylor, BJ, McKeown, M. (e-pub 2006) A double-switch system regulates male courtship behavior in male and female Drosophila melanogaster. Nature Genetics DOI 10.1038/Ng1908. (2006)
  • Ditch, L.M., Shirangi, T., Pitman, J.L., Latham, K.L., Finley, K.D., Edeen, P.T., Taylor, B.J., McKeown, M. (2004 e-pub, 2005 print) Drosophila retained/dead ringer is necessary for neuronal pathfinding, female receptivity and repression of fruitlessindependent male courtship behaviors. Development 132:155-164. (2005)
  • Tsai CC, Kao HY, Mitzutani A, Banayo E, Rajan H, McKeown M, Evans RM. (2004) Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc Natl Acad Sci U S A. 101:4047-52 (2004)
  • 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 . (2003)
  • 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 . (2002)
  • Ghbeish, N. and McKeown, M. (2002) Analyzing the repressive function of Ultraspiracle, the Drosophila RXR, in Drosophila eye development. Mech Dev 111, 89-98. (2002)
  • 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 . (2001)
  • 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 . (2001)
  • 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. (2001)
  • 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 . (1999)
  • 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 . (1999)
  • 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. (1999)
  • 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 . (1998)
  • 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 . (1998)
  • 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 . (1997)
  • 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 . (1997)