Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I

Abstract

Evidence from lower eukaryotes suggests that the chromosomal associations of all the structural maintenance of chromosome (SMC) complexes, cohesin, condensin and Smc5/6, are influenced by the Nipbl/Mau2 heterodimer. Whether this function is conserved in mammals is currently not known. During mammalian meiosis, very different localisation patterns have been reported for the SMC complexes, and the localisation of Nipbl/Mau2 has just recently started to be investigated. Here, we show that Nipbl/Mau2 binds on chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes. In spermatocytes, Nipbl/Mau2 then relocalises to chromocenters, whereas in oocytes it remains bound to chromosomal axes throughout prophase to dictyate arrest. The localisation pattern of Nipbl/Mau2, together with those seen for cohesin, condensin and Smc5/6 subunits, is consistent with a role as a loading factor for cohesin and condensin I, but not for Smc5/6. We also demonstrate that Nipbl/Mau2 localises next to Rad51 and γH2AX foci. NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I. However, this is insufficient to result in major meiotic malfunctions, and the chromosomal associations of the synaptonemal complex proteins and the three SMC complexes appear cytologically indistinguishable in wild-type and Nipbl+/− spermatocytes.

PDS5 proteins regulate the length of axial elements and telomere integrity during male mouse meiosis

“…It is likely that the presence of PDS5A and PDS5B at meiotic chromosome axes occurs in the context of the cohesin complex, as reported for PDS5 in different organisms (van Heemst et al, 1999;Zhang et al, 2005;Ding et al, 2006;Jin et al, 2009), and consistent with the finding that PDS5B co-immunoprecipitates with meiosis-specific cohesin subunits REC8 and SMC1β from mouse spermatocyte extracts (Fukuda and Höög, 2010). Likewise, similar distribution patterns have been previously reported in mouse meiosis for the cohesin cofactors WAPL (Zhang et al, 2008;Brieño-Enríquez et al, 2016), and NIPBL and MAU2 (Visnes et al, 2014). The exception is Sororin, which localizes at the central region of the SC (Gómez at al., 2016;Jordan et al, 2017).…”

High density of REC8 constrains sister chromatid axes and prevents illegitimate synaptonemal complex formation

“…Given the deleterious consequences of loss of SCC and aberrant SC assembly between sister chromatids for meiotic progression and animal fertility, meiocytes need to ensure sufficient REC8 cohesin complexes along chromosome axes, possibly by controlling REC8 expression, stabilization [31] and loading [46]. By comparing the levels of REC8 cohesin in oocytes of young versus aged mice, as well as the effect of REC8 depletion in naturally aged mice, it has been proposed that increased reproductive ageing correlates with depletion of cohesin from chromosome arms and centromeres, leading to erroneous bi-orientation in meiosis I and aneuploidy in eggs [47,48].…”

The cohesin complex in mammalian meiosis

“…The cohesin loading factor NIPBL/SCC2 localizes along chromosome axes during meiotic prophase in fetal oocytes and becomes undetectable after dictyate arrest is commenced (Kuleszewicz, Fu, & Kudo, ; Visnes, Giordano, Kuznetsova, Suja, & Lander, ). Concomitantly, before dictyate arrest, cohesins significantly dissociate from de‐synapsing chromosomes, leaving protein aggregates called polycomplexes (Prieto et al., ).…”