Aurora B and C kinases regulate chromosome desynapsis and segregation during mouse and human spermatogenesis

Abstract

Precise control of chromosome dynamics during meiosis is critical for fertility. A gametocyte undergoing meiosis coordinates formation of the synaptonemal complex (SC) to promote efficient homologous chromosome recombination. Subsequent disassembly of the SC occurs prior to segregation of homologous chromosomes during meiosis I. We examined the requirements of the mammalian Aurora kinases (AURKA, B, and C) during SC disassembly and chromosome segregation using a combination of chemical inhibition and gene deletion approaches. We find that both mouse and human spermatocytes fail to disassemble SC lateral elements when the kinase activity of AURKB and AURKC are chemically inhibited. Interestingly, both Aurkb conditional knockout and Aurkc knockout spermatocytes successfully progress through meiosis and mice are fertile. In contrast, Aurkb, Aurkc double knockout spermatocytes failed to coordinate disassembly of SC lateral elements with chromosome condensation and segregation, resulting in delayed meiotic progression. In addition, deletion of Aurkb and Aurkc led to an accumulation of metaphase spermatocytes, chromosome missegregation, and aberrant cytokinesis. Collectively, our data demonstrates that AURKB and AURKC functionally compensate for one another ensuring successful mammalian spermatogenesis.

Aurora kinase A is essential for meiosis in mouse oocytes

“…Prior AURKA studies used small-molecule inhibitors such as MLN8237 and overexpression to investigate AURKA’s role in mouse oocyte meiotic maturation which do not allow for compensation studies [ 10 , 23 , 24 , 26 , 28 , 31 , 35 ]. To assess compensation and potential AURKA-specific requirements, we deleted Aurka ( Aurka fl/fl ) using Gdf9- Cre; this conditional allele of Aurka has been described elsewhere [ 32 ]. Gdf9 expression begins around day 3 after birth in prophase I-arrested oocytes; these oocytes already completed early prophase I events such as chromosome synapsis and recombination.…”

“…But, in oocytes, AURKC outcompetes AURKB and takes over this CPC role [ 29 , 30 ]. Furthermore, oocytes can complete meiosis in the absence of both AURKB and AURKC because AURKA can function in the CPC; this is specific to oocytes because this compensation does not occur in HeLa cells or in spermatocytes [ 31 , 32 ]. However, although AURKA can compensate, it is not complete because a subset of oocytes arrest in metaphase I with short spindles.…”

Phospho-Regulation of Meiotic Prophase

“…In S. cerevisiae , several kinases have been implicated in SC disassembly, including CDK, DDK, Cdc5 PLK , and Ipl1 Aurora B ( Sourirajan and Lichten, 2008 ; Jordan et al, 2009 ; Argunhan et al, 2017 ). PLK and Aurora B and C kinases are also required for desynapsis in mammals ( Jordan et al, 2012 ; Wellard et al, 2020 ). SC disassembly in S. cerevisiae is tied to the successful completion of meiotic DSB repair through the control of Cdc5 PLK expression, which is maintained at a low level by proteasome-dependent degradation during meiotic prophase ( Okaz et al, 2012 ) and whose expression is regulated at the transcriptional level by Mek1 CHK2 ( Tung et al, 2000 ; Pak and Segall, 2002b ; Chen et al, 2018 ).…”

A Catalog of Human Genes Associated With Pathozoospermia and Functional Characteristics of These Genes

“…The results obtained are in good agreement with the idea that the cellular processes mentioned above (DNA replication, chromosome segregation, formation of a synaptonemal complex) are essential for the formation of a mature sperm cell ( Hann et al, 2011 ; Fowler et al, 2019 ) and at the same time a complex cellular apparatus is formed that ensures the movement of spermatozoa ( O’Donnell, 2014 ; Pereira et al, 2017 ; Cannarella et al, 2020 ). In particular, proteins involved to synaptonemal complex assembly are crucial for spermatogenesis ( Wellard et al, 2020 ). It was shown that infertile men were characterized by increased levels of sperm aneuploidy likely due to increased errors in meiotic recombination and chromosome synapsis ( Tempest, 2011 ).…”