The importance of dietary retinol (vitamin A) for normal spermatogenesis and other aspects of male fertility has been recognized for many years. Animals deprived of vitamin A in their diet exhibit a variety of abnormalities, including male sterility. The requirement for dietary retinol raise interesting question concerning the function of retinoids in the testis, with regard to both their targets which are required for spermatogenesis to occur as well as to their metabolism with various testicular compartments. The ability to mutate endogenous genes involved in the pathways by which vitamin A elicits its effects in the mouse model system has enhanced our understanding of the diverse functions of the retinoids and has opened the opportunity for understanding the molecular basis of their functions. Studies generating mutations in specific receptors for vitamin A metabolites have clearly shown a role for the retinoid receptor RAR-alpha and RXR-beta genes in spermatogenesis. To further our understanding of the role of vitamin A in controlling spermatogenesis, this project will 1) Characterize the phenotypic abnormalities resulting in male sterility in the recently generated strains of mice mutated in RAR-alpha and RXR-beta, with particular emphasis on the developmental etiology of the abnormalities in the testis; 2) Test the hypothesis that the effects of the RAR-alpha and RXR-beta mutations on spermatogenesis are essentially phenocopied by vitamin A- deficiency in mice by comparing the spermatogenic abnormalities in the mutant strain mice with mice which have been vitamin A-deficient from birth, and 3) Explore the role of the RAR-alpha gene in the progression of spermatogenesis, specifically in germ cells. The hypothesis to be tested is that RAR-alpha has distinct functions in the germ line versus somatic cells. Furthermore, it is hypothesized that within the germ line lineage, RAR-alpha may have different functions at different stages of the developmental pathway. To distinguish these functions, it will be necessary to interfere with the function of the RAR-alpha gene selectively in one or the other cell types. To mutate its function in the germ line, conditional knockout mutations will be generated in RAR-alpha uniquely in germ cells at specific stages of development. This will be accomplished by mating mice carrying RAR-alpha flanked by loxP sites with mice carrying a transgene with Cre recombinase driven by regulatory elements driving expression specifically in spermatogonia, early pachytene spermatocytes, and early spermatids, respectively.

Project Start
2002-06-01
Project End
2003-05-31
Budget Start
Budget End
Support Year
5
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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