Abstract
Mammalian sperm feature a specialized secretory organelle on the anterior part of the sperm nucleus, the acrosome, which is essential for male fertility. It is formed by a fusion of Golgi-derived vesicles. We show here that the predominantly Golgi-resident Na+/H+ exchanger NHE8 localizes to the developing acrosome of spermatids. Similar to wild-type mice, Nhe8-/- mice generated Golgi-derived vesicles positive for acrosomal markers and attached to nuclei, but these vesicles failed to form large acrosomal granules and the acrosomal cap. Spermatozoa from Nhe8-/- mice completely lacked acrosomes, were round-headed, exhibited abnormal mitochondrial distribution, and displayed decreased motility, resulting in selective male infertility. Of note, similar features are also found in globozoospermia, one of the causes of male infertility in humans. Germ cell-specific, but not Sertoli cell-specific Nhe8 disruption recapitulated the globozoospermia phenotype, demonstrating that NHE8's role in spermiogenesis is germ cell-intrinsic. Our work has uncovered a crucial role of NHE8 in acrosome biogenesis and suggests that some forms of human globozoospermia might be caused by a loss of function of this Na+/H+ exchanger. It points to NHE8 as a candidate gene for human globozoospermia and a possible drug target for male contraception.
Highlights
Mammalian sperm feature a specialized secretory organelle on the anterior part of the sperm nucleus, the acrosome, which is essential for male fertility
The importance of organellar Naϩ/Hϩ exchanger (NHE) is underscored by mutations in NHE6 and NHE9 that lead to neurological disorders such as autism and epilepsy in humans [20, 21]
NHE8 expression was prominent in kidney, testes, and epididymis, but very low in the female reproductive system (Fig. 1B)
Summary
Organellar NHEs may regulate luminal ion concentrations, in particular the pH, of organelles in the secretory and endocytic pathways. These organelles display distinct, mostly acidic, luminal pH, which is crucial for organellar function (10 –12). Loss of the socalled sperm NHE (sNHE, a member (SLC9C1) of the SLC9C gene family) drastically reduces sperm motility and causes male infertility [32]. Loss of NHE8 disrupts acrosome formation in mice germ cells produced round-headed spermatozoa lacking the acrosomal cap. This resembles human globozoospermia which likewise is associated with infertility. Our work suggests NHE8 as a candidate gene for human globozoospermia and as a possible drug target for male contraception
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