Investigating the contribution of miR-34/449 to mammalian spermatogenesis
Adriano Biasini | Zamore Research Group | The Lalor Foundation Fellowship Award
Male infertility impacts >10% of couples trying to conceive, yet the molecular causes of this disease remain mostly indeterminate. The expression of microRNAs (miRNAs), a class of small regulatory RNAs that post-transcriptionally regulate gene expression, is often aberrant in infertile men, and disruption of miRNA biogenesis blocks germ cell development in mice. One family of miRNAs in particular, the miR-34/449-5p family, accounts for >40% of miRNAs in male mouse meiotic germ cells. Reduction of miR-34/449-5p family members in human seminal plasma was linked with oligoasthenoteratozoospermia and sertoli cell only syndrome. In mice, constitutive depletion of all miR-34/449-5p family members leads to oligoasthenoteratozoospermia, infertility, defective neurodevelopment, and perinatal lethality due to aberrant somatic ciliogenesis. Given the essential role of the miR-34/449-5p family in ubiquitous somatic ciliogenesis, I employed mouse germ cell-specific mutants of these miRNAs. These mutants are infertile bu otherwise physically indistinguishable from control mice. The cell-type-specific comparisons of mutant and control mice have enabled identifying molecular targets of these miRNAs in male germ cells. In the coming year I propose to confirm the importance of miR-34/449-5p-dependent repression of these targets for spermatogenesis, though genetic and biochemical approaches. The findings from this study promise to inform on potential treatments of male infertility.
