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

Abstract

SUMMARYSperm-head elongation and acrosome formation, which take place during the last stages of spermatogenesis, are essential to produce competent spermatozoa that are able to cross the oocyte zona pellucida and to achieve fertilization. During acrosome biogenesis, acrosome attachment and spreading over the nucleus are still poorly understood and to date no proteins have been described to link the acrosome to the nucleus. We recently demonstrated that a deletion of DPY19L2, a gene coding for an uncharacterized protein, was responsible for a majority of cases of type I globozoospermia, a rare cause of male infertility that is characterized by the exclusive production of round-headed acrosomeless spermatozoa. Here, using Dpy19l2 knockout mice, we describe the cellular function of the Dpy19l2 protein. We demonstrate that the protein is expressed predominantly in spermatids with a very specific localization restricted to the inner nuclear membrane facing the acrosomal vesicle. We show that the absence of Dpy19l2 leads to the destabilization of both the nuclear dense lamina (NDL) and the junction between the acroplaxome and the nuclear envelope. Consequently, the acrosome and the manchette fail to be linked to the nucleus leading to the disruption of vesicular trafficking, failure of sperm nuclear shaping and eventually to the elimination of the unbound acrosomal vesicle. Finally, we show for the first time that Dpy19l3 proteins are also located in the inner nuclear envelope, therefore implying that the Dpy19 proteins constitute a new family of structural transmembrane proteins of the nuclear envelope.KEY WORDS: Dpy19l2, Acrosome biogenesis, Globozoospermia, Nuclear envelope, Nuclear lamina, Spermiogenesis, MouseAbsence of Dpy19l2, a new inner nuclear membrane protein, causes globozoospermia in mice by preventing the anchoring of the acrosome to the nucleus

Protein phospholipase C Zeta1 expression in patients with failed ICSI but with normal sperm parameters

“…The SF1 sample was prepared once and used for all Immunoblots theca and equatorial regions [27,28], which are the sites where purportedly PLCZ1 is located [14,29]. In this vein, it was first reported that globozoospermic sperm from patients that failed ICSI showed reduced or absent expression of PLCZ1 [14], and a recent study has extended the association of globozoospermia and infertility to the mouse, as the loss or point mutations in the DPY19L2 gene, which encodes for an inner nuclear membrane protein, is associated with disruption of the sperm perinuclear area, globozoospermia and infertility in this species [30]. Thus, it appears that abnormal sperm head organization, especially in the perinuclear theca and equatorial regions, which may affect the anchoring and/or the stability of PLCZ1, are associated with inability of the sperm to initiate [Ca 2+ ] i responses and egg activation.…”

Atg7 is required for acrosome biogenesis during spermatogenesis in mice

“…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%.…”

“…Once Atg7 was knocked out, cells failed to properly induce p21-CDKN1A expression, resulting in augmented DNA damage with increased p53-dependent apoptosis. The cell cycle-specific role of Atg7 neither requires its E1-like enzymatic activity nor exists in other autophagy-related genes such as Atg5 or Atg6 [35]. Thus, it is most likely that the cell death in the tubule lumens of the testes is dependent on the cell cycle regulatory function of Atg7 rather than its E1-like enzymatic activity.…”

Ultrastructure of Spermatozoa from Infertility Patients

“…The protein products of the two genes occur in the Golgi apparatus and are involved in vesicular trafficking, which is necessary for acrosome biogenesis in spermatids during spermiogenesis [49]. A deletion of DPY19L2 was observed in the majority of total globozoospermia cases; Dpy19l3 protein is essential for a nuclear flattening and the formation of the acrosome [50].…”