Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice

Abstract

Sirt1 is a member of the sirtuin family of proteins and has important roles in numerous biological processes. Sirt1 −/− mice display an increased frequency of abnormal spermatozoa, but the mechanism of Sirt1 in spermiogenesis remains largely unknown. Here, we report that Sirt1 might be directly involved in spermiogenesis in germ cells but not in steroidogenic cells. Germ cell-specific Sirt1 knockout mice were almost completely infertile; the early mitotic and meiotic progression of germ cells in spermatogenesis were not obviously affected after Sirt1 depletion, but subsequent spermiogenesis was disrupted by a defect in acrosome biogenesis, which resulted in a phenotype similar to that observed in human globozoospermia. In addition, LC3 and Atg7 deacetylation was disrupted in spermatids after knocking out Sirt1, which affected the redistribution of LC3 from the nucleus to the cytoplasm and the activation of autophagy. Furthermore, Sirt1 depletion resulted in the failure of LC3 to be recruited to Golgi apparatus-derived vesicles and in the failure of GOPC and PICK1 to be recruited to nucleus-associated acrosomal vesicles. Taken together, these findings reveal that Sirt1 has a novel physiological function in acrosome biogenesis.

NAD+-dependent deacetylase SIRT1 is essential for meiotic progression and controls repair-recombination efficiency

“…We found similar number of cells in leptotene, zygotene, pachytene and diplotene stages between Sirt1 WT and Sirt1 Δmeio mice, both in young adults and during first wave of spermatogenesis (Figs 2A-2D). Importantly, unlike the phenotypes observed earlier when Sirt1 was knocked out in pre-meiotic stages [17, 22], we did not see any change in the relative percentage of pachytene cells. Further, we also found no abnormalities in terms of either desynapsis or breaks, both in autosomes and in sex chromosomes.…”

“…Loss-of-function mutants of SIRT1 in testis have indicated that it is indispensable for spermatogenesis [17, 19-22, 24]. Absence of SIRT1 has been shown to induce apoptosis and loss of meiotic populations, for example when Sirt1 was knocked out using the pre-meiotic Stra8-Cre [17].…”

“…Absence of SIRT1 has been shown to induce apoptosis and loss of meiotic populations, for example when Sirt1 was knocked out using the pre-meiotic Stra8-Cre [17]. While, recent reports have provided some insights into its role in post-meiotic phases [17, 22], its importance in meiotic progression (specifically given its high expression in spermatocytes) remains to be unraveled. Our study, which has employed Spo11-Cre to knockout Sirt1 only in spermatocytes, clearly shows that it plays a key role in meiotic progression.…”

“…Not surprisingly therefore, various models of SIRT1 loss of function and testis-specific conditional mutants have been shown to cause sterility [17, 19-24]. While many of these reports have provided insights into the role of SIRT1 in post-meiotic maturation [17, 22], its relevance during meiosis has not been addressed. Although, knocking out Sirt1 using Stra8-Cre led to abnormal spermatogenesis and reduced fecundity, any potential meiotic defects were poorly characterized [17].…”

Absence of Sirtuin 1 impairs the testicular development in cattleyak by inactivating SF‐1

“…Whole body Sirt1 knockout male mice are infertile with defective hypothalamus‐pituitary gonadotropin signalling and increased frequency of abnormal spermatozoa (Kolthur‐Seetharam et al., 2009). Conditional knockout Sirt1 in mice germ cells causes delayed spermatogenesis and abnormal acrosome biogenesis (Bell et al., 2014; Liu et al., 2017). These results indicate that SIRT1 plays diverse and irreplaceable roles in male mice reproduction.…”