Cohesin Removal along the Chromosome Arms during the First Meiotic Division Depends on a NEK1-PP1γ-WAPL Axis in the Mouse

Abstract

Summary Mammalian NIMA-like kinase-1 (NEK1) is a dual-specificity kinase highly expressed in mouse germ cells during prophase I of meiosis. Loss of NEK1 induces retention of cohesin on chromosomes at meiotic prophase I. Timely deposition and removal of cohesin is essential for accurate chromosome segregation. Two processes regulate cohesin removal: a non-proteolytic mechanism involving WAPL, Sororin, and PDS5B and direct cleavage by Separase. Herein, we demonstrate a role for NEK1 in the regulation of WAPL loading during meiotic prophase I, via an interaction between NEK1 and PDS5B. This regulation of WAPL by NEK1-PDS5B is mediated by the protein phosphatase PP1γ, which both interacts with, and is a phosphotarget, of NEK1. Taken together, our results reveal that NEK1 phosphorylates PP1γ leading to dephosphorylation of WAPL, which in turn results in its retention on chromosome cores to promote loss of cohesion at the end of prophase I in mammals.

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).…”

“…6J-L) and AEs/LEs ( Fig. 6M-O), respectively, as previously reported in wild-type spermatocytes (Brieño-Enríquez et al, 2016;Gómez et al, 2016;Jordan et al, 2017). Centromeric cohesion defects were not evident in deficient Pds5AB zygotene and early pachytene spermatocytes, as kinetochore signals appeared unaltered at the ends of AEs/LEs or SCs, respectively, as in Pds5AB proficient mid pachytene spermatocytes ( Fig.…”

“…However, there are few studies describing the dynamics and involvement of cohesin cofactors during mammalian meiosis. WAPL decorates the AEs/LEs of chromosomes in mouse oocytes (Zhang et al, 2008) and spermatocytes, where it is involved in the removal of arm cohesion by the end of prophase I (Brieño-Enríquez et al, 2016). Unexpectedly, Sororin has been detected at the SC central region, unlike the cohesin subunits and WAPL (Gómez et al, 2016;Jordan et al, 2017).…”

SWITCH 1/DYAD is a novel WINGS APART-LIKE antagonist that maintains sister chromatid cohesion in meiosis

“…In contrast, WAPL has been found to remove meiotic cohesin at late prophase in most if not all organisms studied including Arabidopsis and other plants 11,14,[25][26][27] . Thus, it remains a puzzle how the activity of WAPL is inhibited in early meiotic prophase I especially since no obvious sequence homolog of Sororin or Dalmatian has been identified in the plant lineage and other major branches of the eukaryotic kingdom 28 .…”

Cyclin N-Terminal Domain-Containing 1 (CNTD1) coordinates meiotic crossover formation with cell cycle progression in a cyclin-independent manner

“…Cultures were performed as described elsewhere 61,62 , with some modifications. Testis extracts were dissected into 1 x PBS and incubated in a shaking water bath at 34˚C, 150rpm 850 in 2 mg/ml Collagenase (Sigma C5138) in 1 x PBS for 15 minutes.…”