Distinct prophase arrest mechanisms in human male meiosis

Abstract

To 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.

Disruptive natural selection by male reproductive potential prevents underexpression of protein-coding genes on the human Y chromosome as a self-domestication syndrome

“…3 e). A keyword search in PubMed produced a clinical report [ 69 ] that identified ZFY overexpression in spermatocytes as a physiological marker of meiotic arrest leading to azoospermia and infertility. Within applicability limitations of these clinical observations [ 69 ], we predicted two candidate SNP markers (rs1388535808 and rs996955491) of a decrease in male reproductive potential, as readers can see in Table S 3 .…”

In Vitro Meiosis of Male Germline Stem Cells

“…Both in mouse (de Rooij and de Boer, 2003;Hamer et al, 2008) and in human (Jan et al, 2018), failure of meiotic DSB repair or chromosome synapsis leads to meiotic prophase arrest and subsequent spermatocyte apoptosis. Meiotic arrest prevents the occurrence of univalent chromosomes at the first meiotic M phase, which otherwise could lead to improper chromosome alignment during the first meiotic division and subsequent formation of aneuploid gametes.…”

“…Meiotic spread preparations were prepared as previously described (Jan et al, 2018). Alternatively, all cultured cells, including non-adherent cells, were spread on the slides using a cytospin (CELLSPIN, 521-1990, VWR).…”

“…Importantly, in many cases, for instance, when the absence of haploid spermatids is caused by meiotic arrest (Jan et al, 2018), the patient still has spermatogonial stem cells (SSCs). SSCs are adult male GSCs that, via a perfect balance between self-renewal and differentiation, ensure lifelong sperm production.…”

Microarray meta‐analysis identifies candidate genes for human spermatogenic arrest

“…Studies on both animal and human testes have revealed that many cell cycle‐associated genes are involved in dysfunctional spermatogenesis (Jan et al, ; Wolgemuth, Manterola, & Vasileva, ), but the cell cycle activity of germ cells in human infertility remains poorly understood. Spermatogonia are the main cells responsible for the activity of the mitotic cell cycle in pre‐meiotic arrest.…”