FUNCTIONAL ROLE OF MDAZ IN INFERTILITY

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DESCRIPTION: (Adapted from applicant's description): Approximately 10% of couples world-wide are affected by reduced rates of fertility and approximately half of these cases result from the absence of sperm production (azoospermia) in males. Cytological analysis of patients with azoospermia identified a deletion on the Y chromosome in a significant proportion of cases implying a genetic component to the phenotype. This region was proposed to contain an Azoospermia Factor (AZF). Subsequent analysis of this region identified three distinct genes as AZF candidates one of which was termed Deleted in Azoospermia (DAZ). Interestingly, the mouse homologue of DAZ (mDAZ) is autosomal. Homozygous disruption of the mDAZ gene in mice results in the absence of germ cells beyond the spermatogonial stage demonstrating the significance of DAZ/mDAZ in spermatogenesis. The DAZ gene encodes a germ cell- restricted cytoplasmic RNA-binding protein. Although the function of DAZ is unknown, it appears to regulate the cytoplasmic metabolism of a target mRNA(s) essential in spermatogenesis. Despite the identification of the DAZ gene, progress into the function of its gene product and how it contributes to azoospermia is limited without identification of the cognate mRNA substrate that it binds to and regulates. We have recently devised a novel strategy to identify natural cognate mRNA bound by RNA-binding proteins. This technique enables rapid identification and cloning of specific cellular mRNA bound by an RNA-binding protein. The objective of this proposal is to identify the natural mRNA(s) which are bound by the mDAZ protein (AIM 1) and characterize the mechanism by which mDAZ regulates these target genes and how it contributes to spermatogenesis (AIM 2). This will provide valuable insight into the function of DAZ in the pathogenesis of azoospermia, eventually leading to the design of therapeutic strategies in affected individuals. Understanding how these proteins normally function in sperm production will also provide novel strategies in male contraception.