Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

Abstract

The development and function of male gametes is critically dependent on a dynamic microtubule network, yet how this is regulated remains poorly understood. We have recently shown that microtubule severing, via the action of the meiotic AAA ATPase protein clade, plays a critical role in this process. Here, we sought to elucidate the roles of spastin, an as yet unexplored member of this clade in spermatogenesis. Using a SpastKO/KO mouse model, we reveal that spastin loss resulted in a complete loss of functional germ cells. Spastin plays a critical role in the assembly and function of the male meiotic spindle. Consistent with meiotic failure, round spermatid nuclei were enlarged, indicating aneuploidy, but were still able to enter spermiogenesis. During spermiogenesis, we observed extreme abnormalities in manchette structure, acrosome biogenesis, and commonly, a catastrophic loss of nuclear integrity. This work defines a novel and essential role for spastin in regulating microtubule dynamics during spermatogenesis and is of potential relevance to patients carrying spastin variants and the medically assisted reproductive technology industry.

Epsilon tubulin is an essential determinant of microtubule-based structures in male germ cells

“…This aligns with previous localization of TUBE1 to the midbody during mitosis (Chang and Stearns, 2000 ) and supports that TUBE1 functions alongside the microtubule severing machinery in spermatogenesis. In accordance, binucleated spermatids were seen in KATNAL1, KATNB1 and spastin loss-of-function (LOF) models (Cheers et al, 2023 ; Dunleavy et al, 2023 ; Dunleavy et al, 2021 ).…”