Atg7 is required for acrosome biogenesis during spermatogenesis in mice

Abstract

The acrosome is a specialized organelle that covers the anterior part of the sperm nucleus and plays an essential role in the process of fertilization. The molecular mechanism underlying the biogenesis of this lysosome-related organelle (LRO) is still largely unknown. Here, we show that germ cell-specific Atg7-knockout mice were infertile due to a defect in acrosome biogenesis and displayed a phenotype similar to human globozoospermia; this reproductive defect was successfully rescued by intracytoplasmic sperm injections. Furthermore, the depletion of Atg7 in germ cells did not affect the early stages of development of germ cells, but at later stages of spermatogenesis, the proacrosomal vesicles failed to fuse into a single acrosomal vesicle during the Golgi phase, which finally resulted in irregular or nearly round-headed spermatozoa. Autophagic flux was disrupted in Atg7-depleted germ cells, finally leading to the failure of LC3 conjugation to Golgi apparatus-derived vesicles. In addition, Atg7 partially regulated another globozoospermia-related protein, Golgi-associated PDZ-and coiled-coil motif-containing protein (GOPC), during acrosome biogenesis. Finally, the injection of either autophagy or lysosome inhibitors into testis resulted in a similar phenotype to that of germ cell-specific Atg7-knockout mice. Altogether, our results uncover a new role for Atg7 in the biogenesis of the acrosome, and we provide evidence to support the autolysosome origination hypothesis for the acrosome.

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

“…8E to H). To further prove that PDLIM1 was degraded through the autophagy-lysosome pathway, 2 acidic lysosome inhibitors, ammonium chloride (NH 4 Cl) and chloroquine (CQ), 23 were used to inhibit the autophagy-lysosome pathway. After treatment with lysosome inhibitors, PDLIM1 protein significantly accumulated (Fig.…”

“…23 Each male mouse (8 or 9 wk) was caged with 2 CD1 females (7 or 8 wk), and their vaginal plugs were checked every morning. The number of pups in each cage was counted within a week of birth.…”

“…20 Autophagy participates in cell growth, adaptation to stress conditions, anti-aging mechanisms, intracellular quality control, renovation during development and differentiation and the biogenesis of organelles such as cilia and acrosome. 21,[23][24][25] Autophagy is also active in Sertoli cells, [26][27][28][29] where it is involved in the clearance of SHBG/ABP that is selectively regulated by testosterone. 26 However, the role of autophagy in Sertoli cells is still largely unknown.…”

Mfsd14a (Hiat1) gene disruption causes globozoospermia and infertility in male mice

“…Other mutant mice have been described with defects in acrosome biogenesis and globozoospermia, including those with disruption of the Atg7 (Wang et al 2014), Csnk2a2 (Xu et al 1999), Dpy19l2 (Pierre et al 2012), Gopc (Yao et al 2002), Agfg1 (Hrb) (Kang-Decker et al 2001), Hsp19β1 (Audouard & Christians 2011), Pick1 (Xiao et al 2009), Smap2 (Funaki et al 2013), Spaca1 (Fujihara et al 2012) and Vps54 (Paiardi et al 2011) genes. The similarity in the phenotype of these mutant mice suggests that these genes form a functional network required for the ultrastructural changes to the sperm head.…”

“…which include Atg7 (Wang et al 2014), Csnk2a2 (Xu et al 1999), Dpy19l2 (Pierre et al 2012), Gopc (Yao et al 2002), Agfg1 (Hrb) (Kang-Decker et al 2001), Hsp19β1 (Audouard & Christians 2011), Pick1 (Xiao et al 2009), Smap2 (Funaki et al 2013), Spaca1 (Fujihara et al 2012) and Vps54 (Paiardi et al 2011). Similarly, causative mutations of globozoospermia have been identified in humans inclu ding DPY19L2 (Harbuz et al 2011, Koscinski et al 2011, PICK1 (Liu et al 2010) and SPATA16 (Dam et al 2007b).…”