Distinct prophase arrest mechanisms in human male meiosis

Abstract

To prevent chromosomal aberrations to be transmitted to the offspring, strict meiotic checkpoints are in place to remove aberrant spermatocytes. However, in about 1% of all males these checkpoints cause complete meiotic arrest leading to azoospermia and subsequent infertility. We here unravel two clearly distinct meiotic arrest mechanisms that act during the prophase of human male meiosis. Type I arrested spermatocytes display severe asynapsis of the homologous chromosomes, disturbed XY-body formation and increased expression of the Y-chromosome encoded gene ZFY and seem to activate a DNA damage pathway leading to induction of p63 mediated spermatocyte elimination. Type II arrested spermatocytes display normal chromosome synapsis, normal XY-body morphology and meiotic crossover formation but have a lowered expression of several cell cycle regulating genes and fail to properly silence the X-chromosome encoded gene ZFX. Discovery and understanding of these meiotic arrest mechanisms increases our knowledge on how genomic stability is guarded during human germ cell development.