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Return to: College of Biological Sciences: Medical School: U of M Home |
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Areas of Research Strength: Sex determination regulation of gene expression back to top |
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Research Techniques: Molecular biology genetics transgenics mouse gene knockouts back to top |
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Research Interests: The Zarkower laboratory studies the process of sex Determination, which is the mechanism by which an animal is directed to become male or female during development. As a model, we initially studied the nematode worm C. elegans, because it has many experimental advantages, including fast and powerful genetics, ease of gene manipulation, a fixed cell lineage, and a fully sequenced genome. More recently we also have studied sex determination in the mouse, concentrating on aspects of sex determination that may be conserved throughout the animal kingdom. In C. elegans we are interested in a master regulatory gene called tra-1 and the genes it controls. The activity of tra-1 controls all aspects of sexual development in the nematode: if tra-1 is active the animal is female, and if it is inactive the animal is male. One gene tra-1 controls is mab-3. This gene is required for several aspects of male development, including formation of the male peripheral nervous system, regulation of yolk proteins, and male mating behavior. We showed several years ago that mab-3 is related to a fruit fly sex determining gene called doublesex. This is the first example of an evolutionarily conserved family of sex determining genes. The Doublesex and MAB-3 proteins contain a new type of DNA binding domain that the lab has named the DM domain. We found that MAB-3 can act as a transcriptional repressor and are investigating how MAB-3 controls male sense organ development. We are looking for other genes that are regulated by tra-1 by various genetic and molecular screens, concentrating on sexual differentiation of the somatic gonad and sensory nervous system. We have identified a number of genes in these screens and are studying how they help direct sexually dimorphic development. Recently we identified human and mouse genes that resemble mab-3 and doublesex. One gene, DMRT1, maps to a short region of chromosome 9 that is required for male development. The mouse homologue, Dmrt1, is expressed in the embryonic gonad during the time that the male and female gonads become distinct. We made a mouse "knockout" of Dmrt1, and found that it causes testis defects similar to those of humans with deletions of chromosome 9. Dmrt1 is expressed male-specifically in the early gonads of reptiles (temperature-dependent sexdetermination) and birds (ZZ/ZW sex determination), suggesting a widely conserved role in vertebrate male development. We are studying how Dmrt1 regulates different aspects of testis differentiation. We have found four more DM domain genes that are expressed in the embryonic gonad, including one that is ovary-specific, and we are currently studying their roles in sexual development. back to top |
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Selected Publications: Kim, S., Namekawa, S.H., Niswander, L.M., Ward, J.O., Lee, J.T., Bardwell, V.J., and Zarkower, D. (2007) A mammal-specific Doublesex homolog required for sex chromatin modification during male meiosis. PLoS Genetics, in press. Fahrioglu, U., Murphy, M.W., Zarkower, D., and Bardwell, V.J. (2007) mRNA expression analysis and the molecular basis of neonatal testis defects in Dmrt1 mutant mice. Sexual Development 1:42-58. Balciuniene, J., Bardwell, V.J., and Zarkower D. (2006) Mice mutant for the DM domain gene Dmrt4 are viable and fertile but have polyovular follicles. Mol. Cell. Biol. 26:9884-8991. Ross, J.M., Kalis, A., and D. Zarkower. (2005) The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating bHLH proteins. Developmental Cell 8:881-892 Chang, W., Lloyd, C.E., and D. Zarkower. (2005) DSH-2 regulates asymmetric cell division in the early C. elegans somatic gonad. Mechanisms of Development 122:781-789 Thoemke, K., Yi, W., Ross, J.M., Kim, S., Reinke, V., and D. Zarkower. (2005) Genome-wide analysis of sex-enriched gene expression during C. elegans larval development. Developmental Biology 284:500-508 Chang W, Tilmann C, Thoemke K, Markussen F-H, Mathies LD, Kimble J, and Zarkower D (2004) A forkhead protein controls sexual identity of the C. elegans male gonad. Development. 131: 1425-1436. Volff J-N, Zarkower D, Bardwell VJ, and M Schartl (2003) Evolutionary dynamics of the DM domain gene family in metazoans. J Mol Evol 57 Suppl. 1:S241-249. Loffler KA, Zarkower D, P Koopman (2003) Aetiology of blepharophimosis-ptosis-epicanthus inversus syndrome: FOXL2 is a conserved, early-acting gene in vertebrate ovarian development. Endocrinology 144: 3237-3243. Ross, J., and Zarkower, D. (2003) Polycomb group regulation of Hox gene expression in C. elegans. Developmental Cell 4:891-901. Shetty S, Kirby P, Zarkower D, Graves JA (2002) DMRT1 in a ratite bird: evidence for a role in sex determination and discovery of a putative regulatory element. Cytogenet Genome Res 99(1-4) 245-51. Zarkower, D. (2001). Establishing sexual dimorphism: conservation amidst diversity? Nature Reviews Genetics 2:175-185 Lum DH, Kuwabara PE, Zarkower D, and Spence AM (2000). Direct protein-protein interaction between the intracellular domain of TRA-2 and the transcription factor TRA-1A modulates feminizing activity in C. elegans. Genes Dev.14:3153-65 Raymond, C.S., Murphy, M.W., O©&Mac246;Sullivan, M.G., Bardwell, V.J., and Zarkower, D. (2000). Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 14:2587-2595. Yi, W., Ross, J.M., and Zarkower, D. (2000). mab-3 is a direct tra-1 target gene regulating diverse aspects of C. elegans male sexual development and behavior. Development 127:4469-4480. Kettlewell, J.R., Raymond, C.S., and Zarkower, D. (2000). Temperature-dependent expression of turtle Dmrt1 prior to sexual differentiation. Genesis 26:174-178. Raymond, C.S., Kettlewell, JR., Hirsch, B, Bardwell, V.J., and Zarkower, D. (1999). Expression of Dmrt1 in the genital ridge of mouse and chicken embryos suggests a role in vertebrate sexual development. Dev. Biol. 215:208-220. Raymond, C.S., Parker, E.D., Kettlewell, J.R., Brown, L.G., Page, D.C., Kusz, K., Jaruzelska, J., Reinberg, R., Flejter, W.L., Bardwell, V.J., Hirsch, B., and Zarkower, D. (1999). A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. Human Mol. Genet. 8:989-996 Yi, W, and D. Zarkower (1999). Similarity of DNA binding and transcriptional regulation by C. elegans MAB-3 and Drosophila melanogaster DSX suggests conservation of sex determining mechanisms. Development 126:873-881. Raymond, C.S., Shamu, C.E., Shen, M.M., Seifert, K.J., Hirsch, B., Hodgkin, J., and D. Zarkower (1998). Evidence for evolutionary conservation of sex determining genes. Nature 391:691-695. To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed search menu should say PubMed type Zarkower D in the avaliable line back to top |
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