We plan on continuing our studies of mammalian sex determination and differentiation using mice for experimental observations followed by clinical correlations in patients with sexual ambiguity. The first focus will be on the Y chromosomal gene candidate for sex determination recently cloned by Dr. David Page (Zfy). The DNA sequence of this clone predicts a zinc finger, DNA binding protein with probable regulatory properties. We will test its role in sex determination by expression of it, and its antisense, in transgenic mice in order to look for sex reversal. We have developed what we believe is a novel cloning strategy to clone stretches of DNA that will respond to positive regulatory signals from this protein in yeast. This approach may allow us to identify autosomal or X-linked genes involved in sex determination. We will also study Zfy expression in early embryos and in differentiating gonadal tissues of mice and will search for variation in its structure between tow kinds of mouse Y chromosomes which function differently on the C56BL/6J background. Our efforts to detect transcripts in early mouse embryos will use the polymerase chain reaction which has the potential to detect minute amounts of transcription. We have already demonstrated that Y chromosomal clones are very useful in elucidating problems of sexual ambiguity in patients. In addition, analysi of reorganizations of the Y chromosomes such as those that occur in XX male help us to elucidate chromosomal mechanisms during meiosis. Thus, we believe that our studies of sex determination both increase our understanding of mammalian development and provide clinically useful material to aid patients seen in genetics and endocrine clinics.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020670-07
Application #
3319008
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1990-08-01
Project End
1993-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Erickson, R P (1997) Does sex determination start at conception? Bioessays 19:1027-32
Zwingman, T; Fujimoto, H; Lai, L W et al. (1994) Transcription of circular and noncircular forms of Sry in mouse testes. Mol Reprod Dev 37:370-81
Seaver, L H; Grimes, J; Erickson, R P (1994) Female pseudohermaphroditism with multiple caudal anomalies: absence of Y-specific DNA sequences as pathogenetic factors. Am J Med Genet 51:16-21
Ao, A; Erickson, R P; Stalvey, J R (1993) Sites of transcription of the Mullerian inhibiting substance gene in mouse testis. Mol Reprod Dev 35:159-64
Zwingman, T; Erickson, R P; Boyer, T et al. (1993) Transcription of the sex-determining region genes Sry and Zfy in the mouse preimplantation embryo. Proc Natl Acad Sci U S A 90:814-7
Erickson, R P; Zwingman, T; Ao, A (1993) Gene expression, X-inactivation, and methylation during spermatogenesis: the case of Zfa, Zfx, and Zfy in mice. Mol Reprod Dev 35:114-20
Van Dyke, D L; Wiktor, A; Palmer, C G et al. (1992) Ullrich-Turner syndrome with a small ring X chromosome and presence of mental retardation. Am J Med Genet 43:996-1005
Graves, P E; Erickson, R P (1992) An amino acid change in the DNA-binding region of Sry, found in Mus musculus domesticus and other species, does not explain C57BL/6J-YDOM sex-reversal. Biochem Biophys Res Commun 185:310-6
Bailey, W A; Zwingman, T A; Reznik, V M et al. (1992) End-stage renal disease and primary hypogonadism associated with a 46,XX karyotype. Am J Dis Child 146:1218-23
Erickson, R P; Glover, T W; Hall, B K et al. (1991) Polymerase chain reactions with alphoid-repeat primers in combination with Alu or LINEs primers, generate chromosome-specific DNA fragments. Ann Hum Genet 55:199-211

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