In mammals, gonadal sex determination is the process that determines whether the embryonic gonad will develop as testis or as ovary. The long-term objective of this project is a detailed understanding of the genes involved in this binary switching system. The guiding premise of this project is that an abundance of mutations, occurring naturally in both humans and mice, provide powerful points of entry for investigating,the sex-determining mechanism. Such defects in sex-determining genes result, in both humans and in mice, in abnormal sexual differentiation and infertility. A chief goal of the present application is identification, via genetic linkage analysis in mice, of two or more autosomal genes that play critical roles in gonadal sex determination, and analysis of the structure and function of those genes in both mice and humans. Should this line of inquiry lead to the cloning of putative sex-determining genes, the functions of those genes will be tested in transgenic mice. These studies may result in highly defined mouse models of abnormal sexual development. A related goal of the present application is the characterization of human mutations that result in sex reversal. Among the humans mutations to be characterized by detailed studies at the DNA level are: 1) gross structural anomalies of the Y chromosome associated with sex reversal of XX or XY individuals, 2) Y-chromosomal point mutations resulting in ovarian development in XY individuals, and 3) autosomal or X-linked mutations resulting in sex reversal of XX or XY individuals. A third goal of the present application is identification of the biological functions of the mammalian ZFY and ZFX genes, which encode zinc-finger proteins, via manipulations of the genes in cultured cells and in transgenic mice.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD022532-07
Application #
3322164
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1986-12-01
Project End
1997-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Mahaffey, C L; Bayleran, J K; Yeh, G Y et al. (1997) Intron/exon structure confirms that mouse Zfy1 and Zfy2 are members of the ZFY gene family. Genomics 41:123-7
Eicher, E M; Washburn, L L; Schork, N J et al. (1996) Sex-determining genes on mouse autosomes identified by linkage analysis of C57BL/6J-YPOS sex reversal. Nat Genet 14:206-9
Zambrowicz, B P; Findley, S D; Simpson, E M et al. (1994) Characterization of the murine Zfy1 and Zfy2 promoters. Genomics 24:406-8
Zambrowicz, B P; Zimmermann, J W; Harendza, C J et al. (1994) Expression of a mouse Zfy-1/lacZ transgene in the somatic cells of the embryonic gonad and germ cells of the adult testis. Development 120:1549-59
Page, D C; Disteche, C M; Simpson, E M et al. (1990) Chromosomal localization of ZFX--a human gene that escapes X inactivation--and its murine homologs. Genomics 7:37-46
Cantrell, M A; Bicknell, J N; Pagon, R A et al. (1989) Molecular analysis of 46,XY females and regional assignment of a new Y-chromosome-specific probe. Hum Genet 83:88-92
Schwartz, M; Yang, H M; Niebuhr, E et al. (1988) Regional localization of polymorphic DNA loci on the proximal long arm of the X chromosome using deletions associated with choroideremia. Hum Genet 78:156-60
Munke, M; Page, D C; Brown, L G et al. (1988) Molecular detection of a Yp/18 translocation in a 45,X holoprosencephalic male. Hum Genet 80:219-23