University of Minnesota
University of Minnesota
College of Biological Sciences
http://www.cbs.umn.edu/

David Zarkower, PhD

Professor
Director, Developmental Biology Center
612-625-9450
PhD: University of Wisconsin-Madison, 1989

Research Interests:

Sex determination is the process that establishes whether an embryo will become male or female.  Sex determination and the resulting sexual differentiation are fundamental aspects of normal development, and they profoundly shape the anatomy, physiology, and behavior of nearly all animal species.  Moreover, disorders of sexual differentiation (DSDs) are among the most common congenital syndromes and often have serious medical and social consequences.  Research in the Zarkower laboratory aims to uncover the molecular and genetic mechanisms that underlie sexual development.  To accomplish this goal we study model organisms in which powerful genetic, genomic, and molecular approaches are possible, primarily the nematode worm C. elegans and the mouse.


In C. elegans we are interested in the master regulator of sexual differentiation Transformer 1 (TRA-1), which controls all aspects of sexual development, and we have used genome-wide ChIP-seq methods to identify the genes TRA-1 controls.  One such gene is male abnormal 3 (mab-3), which is required for several aspects of male development and behavior.  

mab-3 is related to a fruit fly sex determining gene called doublesex, with both genes containing the “DM domain” DNA binding motif.  This similarity provided the first evidence that sex determination is a deeply conserved process.  We also are interested in how the nematode gonad differentiates into radically different structures in the two sexes and we have used cell-specific mRNA profiling to find genes expressed specifically in the two somatic gonad precursor cells and also expressed differently in the two sexes. 

We have identified a number of human and mouse genes that related to dsx and mab-3. One of these, DMRT1, maps to a short region of human chromosome 9 that is required for male development. We made a mouse "knockout" of Dmrt1 and found that it causes testis defects similar to those of humans with deletions of chromosome 9.  Much recent evidence has implicated Dmrt1 and its close homologs in vertebrate sex determination, in birds, reptiles, fish, and amphibians. We are using genomic approaches including ChIP-chip, ChIP-seq, and expression profiling, coupled with conditional gene targeting to understand how DMRT1 controls testis development and to identify the genes regulated by DMRT1.  This work is ongoing but has already yielded important insights into germ cell pluripotency, testicular germ cell cancer, cell fate reprogramming, and regulation of meiosis.

We also have made mutants of the other six mouse Dmrt genes and are using these to understand their roles in mouse development.

A newer area of research in the lab is evolution of vertebrate sex chromosomes.  To study this we have focused on geckos, a large vertebrate group (~1500 species) in which new sex determining mechanisms have evolved multiple times.  We are combining next-generation sequencing approaches with cytogenetics and phylogenetic analysis to identify transitions between sex determination mechanisms and identify the chromosomes and genes involved.  This will shed important light on chromosome evolution and the origins of vertebrate sex determination.

 


Selected Publications:


DMRT1 Protects Male Gonadal Cells from Retinoid-Dependent Sexual Transdifferentiation.

Minkina A, Matson CK, Lindeman RE, Ghyselinck NB, Bardwell VJ, Zarkower D.
Dev. Cell.2014 May 21. pii: S1534-5807(14)00237-8. doi: 10.1016/j.devcel.2014.04.017. [Epub ahead of print]
PMID: 24856513

Over-expression of DMRT1 induces the male pathway in embryonic chicken gonads.
Lambeth LS, Raymond CS, Roeszler KN, Kuroiwa A, Nakata T, Zarkower D, Smith CA
Dev. Biol. (2014) 389:160-72. PMID: 24576538

Identification of sex-specific molecular markers using restriction site-associated DNA sequencing.
Gamble T, Zarkower D. Mol. Ecol. Resour.(2014) Feb 10. doi: 10.1111/1755-0998.12237. [Epub ahead of print] PMID: 24506574

Anolis sex chromosomes are derived from a single ancestral pair. 
Gamble, T, Geneva, TJ, Glor, RE, and Zarkower D. Evolution (2014) 4:1027-1041.

TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination.
Berkseth M, Ikegami K, Arur S, Lieb JD, Zarkower D. Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16033-8.

A sex-specific transcription factor controls male identity in a simultaneous hermaphrodite.
Chong T, Collins JJ 3rd, Brubacher JL, Zarkower D, Newmark PA. Nat. Commun. 2013;4:1814.

Sex determination.Gamble T, Zarkower D. Curr. Biol. 2012 Apr 24;22(8):R257-62.

Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity.
Matson CK, Zarkower D. Nat. Rev. Genet. 2012 Feb 7;13(3):163-74

DMRT1 prevents female reprogramming in the postnatal mammalian testis.
Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D. Nature. 2011 476:101-104. PMID: 21775990

The mammalian Doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells.
Matson, C.K., Murphy, M.W., Griswold, M.D., Yoshida, S., Bardwell, V.J., and Zarkower, D. (2010) Dev. Cell 19:612-24. PMCID: NIHMS245606

Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis.
Murphy, M.W., Sarver, A..L, Rice, D., Hatzi, K,, Ye, K., Melnick, A., Heckert, L.L., Zarkower, D., and Bardwell, V.J. (2010) Proc. Natl. Acad. Sci. USA 201:13360-5. PMCID: PMC2922116

The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency.(2009)
Krentz, AD, Murphy, MW, Kim, S, Cook, MS, Capel, B, Zhu, R, Matin, A, Sarver, AL, Parker, KL, Griswold, MD, Looijenga, LH, Bardwell, VJ, and Zarkower, D. Proc. Natl. Acad. Sci USA 106:22323-8.

A mammal-specific Doublesex homolog required for sex chromatin modification during male meiosis.(2007)
Kim, S., Namekawa, S.H., Niswander, L.M., Ward, J.O., Lee, J.T., Bardwell, V.J., and Zarkower, D. PLoS Genetics 3:e62. 

The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating DevbHLH proteins.(2005)
Ross, J.M., Kalis, A., and D. Zarkower. Dev. Cell 8:881-892

A forkhead protein controls sexual identity of the C. elegans male gonad.(2004)
Chang W, Tilmann C, Thoemke K, Markussen F-H, Mathies LD, Kimble J, and Zarkower D. Development 131: 1425-1436.

Polycomb group regulation of Hox gene expression in C. elegans.(2003) Ross, J., and Zarkower, D. Dev. Cell 4:891-901.

Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation.(2000)
Raymond, C.S., Murphy, M.W., O'Sullivan, M.G., Bardwell, V.J., and Zarkower, D. Genes Dev. 14:2587-2595.

mab-3is a direct tra-1 target gene regulating diverse aspects of C. elegans male sexual development and behavior.(2000)
Yi, W., Ross, J.M., and Zarkower, D. Development 127:4469-4480.

Evidence for evolutionary conservation of sex determining genes.(1998)
Raymond, C.S., Shamu, C.E., Shen, M.M., Seifert, K.J., Hirsch, B., Hodgkin, J., and D. Zarkower. Nature 391:691-695.
 



To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed
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Office:
5-147A Moos Tower

Lab:
5-143 Moos Tower
P: 612-626-4259