Abstract
Meiosis is a highly conserved process, which is stringently regulated in all organisms, from fungi through to humans. Two major events define meiosis in eukaryotes. The first is the pairing, or synapsis, of homologous chromosomes and the second is the exchange of genetic information in a process called meiotic recombination. Synapsis is mediated by the meiosis-specific synaptonemal complex structure in combination with the cohesins that tether sister chromatids together along chromosome arms through prophase I. Previously, we identified FKBP6 as a novel component of the mammalian synaptonemal complex. Further studies demonstrated an interaction between FKBP6 and the NIMA-related kinase-1, NEK1. To further investigate the role of NEK1 in mammalian meiosis, we have examined gametogenesis in the spontaneous mutant, Nek1kat2J. Homozygous mutant animals show decreased testis size, defects in testis morphology, and in cohesin removal at late prophase I of meiosis, causing complete male infertility. Cohesin protein SMC3 remains localized to the meiotic chromosome cores at diplonema in the Nek1 mutant, and also in the related Fkbp6 mutant, while in wild type cells SMC3 is removed from the cores at the end of prophase I and becomes more diffuse throughout the DAPI stained region of the nucleus. These data implicate NEK1 as a possible kinase involved in cohesin redistribution in murine spermatocytes.
Highlights
Meiosis is a specialized form of cell division that is highly conserved from fungi to humans; beginning with one round of pre-meiotic replication, followed by two rounds of division, to produce haploid gametes for sexual reproduction
Taking into account the smaller body weights of the mutant animals, by measuring testis weight as a percentage of total body weight, the Nek1kat2J/kat2J males exhibit an average reduction in testis weight of 49% (p < 0.0001, unpaired t-test, Figure 1B), which is comparable to other meiotic mutants previously characterized [7]
While NEK1 appears to be largely essential for progression through the first meiotic division, it is important to note that some spermatids were observed in the testes of Nek1kat2J/kat2J males, suggesting that these cells were able to proceed to meiosis II
Summary
Meiosis is a specialized form of cell division that is highly conserved from fungi to humans; beginning with one round of pre-meiotic replication, followed by two rounds of division, to produce haploid gametes for sexual reproduction. The defining stage of meiosis, prophase I [1] encompasses two critical events to ensure faithful completion of meiotic division, namely pairing and synapsis of homologous (maternal and paternal) chromosomes, and the repair of double-strand breaks (DSBs), the latter resulting in the formation of crossover and non-crossovers in a process termed meiotic recombination. In addition to SC formation, homolog synapsis is highly dependent on sister chromatid cohesion (SCC), as mediated by the meiotic cohesins. Until anaphase II, SC proteins are required for cohesin integrity at diplonema [20] This suggests that REC8 might be required for SC axial element formation [21] and subsequent centromere attachment. The intense FKBP6 staining persists into pachynema, and remains until diplonema of late prophase I, when it begins to disappear from the chromosomes, indicating a role in SC assembly/maintenance in mammalian meiosis. We describe in detail the meiotic progression in these mice and the apparent errors in cohesin unloading from the chromosome cores at the end of prophase I
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