Distinct prophase arrest mechanisms in human male meiosis.

Sabrina Z Jan,Geert Hamer,Aldo Jongejan,Saskia K M Van Daalen,Ans M M Van Pelt,Cindy M Korver,Sjoerd Repping

doi:10.1242/dev.160614

Sabrina Z Jan, Geert Hamer + Show 5 more

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https://doi.org/10.1242/dev.160614

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Abstract

ABSTRACTTo prevent chromosomal aberrations being transmitted to the offspring, strict meiotic checkpoints are in place to remove aberrant spermatocytes. However, in about 1% of males these checkpoints cause complete meiotic arrest leading to azoospermia and subsequent infertility. Here, we unravel two clearly distinct meiotic arrest mechanisms that occur during 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, possibly causing spermatocyte apoptosis. 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 silence the X chromosome-encoded gene ZFX. Discovery and understanding of these meiotic arrest mechanisms increases our knowledge of how genomic stability is guarded during human germ cell development.

Highlights

Whereas our somatic bodies inevitably die of old age or disease, our germ cells have to maintain sufficient genomic integrity to pass on our genome to, in principle, endless generations
Type I and II arrested spermatocytes fail to silence the sex chromosomes properly we investigated whether the increased expression of ZFY and ZFX in the meiotic arrest samples could be due to disturbed meiotic sex chromosome silencing
As in mouse (Burgoyne et al, 2009; Jan et al, 2012; Royo et al, 2010), human type I meiotic prophase arrest appears to be characterized by incomplete synapsis of the homologous chromosomes and subsequent failure to silence the sex chromosomes, leading to aberrant expression of the Ychromosomal gene ZFY

Summary

Introduction

Whereas our somatic bodies inevitably die of old age or disease, our germ cells have to maintain sufficient genomic integrity to pass on our genome to, in principle, endless generations. To prevent transmission of aneuploidies or other chromosomal aberrations, strict genome integrity checkpoints exist in the process of meiosis to remove germ cells that fail certain quality checks. In order to generate haploid sperm or oocytes, diploid germ cells undergo two consecutive rounds of chromosome segregation after one round of DNA replication. During meiosis I, the homologous chromosomes, each consisting of one pair of sister chromatids, are segregated, followed by separation of the sister chromatids into haploid cells during meiosis II. Successful meiosis requires that the homologous chromosomes are properly paired and aligned. This is achieved by the induction of DNA double-strand breaks (DSBs) by the protein SPO11 during the prophase of the first

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