Failure of acrosome formation and globozoospermia in the wobbler mouse, a Vps54 spontaneous recessive mutant

Abstract

The acrosome is a unique organelle that plays an important role at fertilization and during sperm morphogenesis and that is absent in globozoospermia, an inherited infertility syndrome in humans. At the light of recent experimental evidence, the acrosome is considered a lysosome-related organelle to whose biogenesis both the endocytic and biosynthetic pathways contribute. Vps54 is a vesicular sorting protein involved in the retrograde traffic; the recessive Vps54(L967Q) mutation in the mouse results in the wobbler phenotype, characterized by motor-neuron degeneration and male infertility. Here we have investigated the spatio-temporal occurrence/progression of the wobbler fertility disorder starting from mice at post-natal day 35, the day of the first event of spermiation. We show that the pathogenesis of wobbler infertility originates at the first spermiogenetic wave, affecting acrosome formation and sperm head elongation. Vps54(L967Q)-labeled vesicles, on the contrary of the wild-type Vps54-labeled ones, are not able to coalesce into a larger vesicle that develops, flattens and shapes to give rise to the acrosome. Evidence that it is the malfunctioning of the endocytic traffic to hamper the development of the acrosome comes out from the study on UBPy. UBPy, a deubiquitinating enzyme, is a marker of acrosome biogenesis from the endocytic pathway. In wobbler spermatids UBPy-positive endosomes remain single, scattered vesicles that do not contribute to acrosome formation. As secondary defect of wobbler spermiogenesis, spermatid mitochondria are misorted; moreover, with the progression of the age/disease also Sertoli-germ cell adhesions are compromised suggesting a derailment in the endocytic route that underlies their restructuring.

Atg7 is required for acrosome biogenesis during spermatogenesis in mice

“…According to these similarities, the acrosome has been postulated to be a modified lysosome [4]. Components of the endocytic machinery, such as Afaf [14], SH3P13 [23], SPE-39 [24], UBPy [25], RasGRF1 [26], and Vps54 [27,28], are involved in the biogenesis of the acrosome [2]. This evidence strongly supports the notion that the acrosome is a novel LRO.…”

“…Ten genes have been found to be associated with globozoospermia, including Csnk2a2 [30], Hrb [3], Gopc [19], Gba2 [31], Zpbp1 [32], Pick1 [11], Vps54 [27], Hsp90b1 [33], Spaca1 [34] and Dpy19l2 [35]. Among 25%.…”

Absence of Dpy19l2, a new inner nuclear membrane protein, causes globozoospermia in mice by preventing the anchoring of the acrosome to the nucleus

“…In mice, a total of eight genes has been described to trigger globozoospermia. The first group of four proteins -Pick1 (Xiao et al, 2009), Gopc (Yao et al, 2002), Vps54 (Paiardi et al, 2011) and Hrb (Kang-Decker et al, 2001), as SPATA16 -controls Golgi vesicles fusion necessary for acrosome formation. The second set of globozoospermia-inducing proteins comprises Zpbp1 (Lin et al, 2007), Ck2Ј (Xu et al, 1999), Hsp90b1 (Audouard and Christians, 2011) and Gba2 (Yildiz et al, 2006), which have more diverse cellular localizations and functions: Zpbp1 and Ck2Ј are proteins of the acrosomal matrix, whereas Hsp90b1 is expressed in the reticulum and Gba2 is expressed in both germ and Sertoli cells.…”

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).…”