Abstract
Study of knockout (KO) mice has helped understand the link between many genes/proteins and human diseases. Identification of infertile KO mice provides valuable tools to characterize the molecular mechanisms underlying gamete formation. The KIAA0319L gene has been described to have a putative association with dyslexia; surprisingly, we observed that homozygous KO males for AU040320, KIAA0319L ortholog, are infertile and present a globozoospermia-like phenotype. Mutant spermatozoa are mostly immotile and display a malformed roundish head with no acrosome. In round spermatids, proacrosomal vesicles accumulate close to the acroplaxome but fail to coalesce into a single acrosomal vesicle. In wild-type mice AU040320 localises to the trans-Golgi-Network of germ cells but cannot be detected in mature acrosomes. Our results suggest AU040320 may be necessary for the normal formation of proacrosomal vesicles or the recruitment of cargo proteins required for downstream events leading to acrosomal fusion. Mutations in KIAA0319L could lead to human infertility; we screened for KIAA0319L mutations in a selected cohort of globozoospermia patients in which no genetic abnormalities have been previously identified, but detected no pathogenic changes in this particular cohort.
Highlights
Spermatogenesis is a complex developmental process by which mammalian spermatozoa, the male haploid germ cells, are produced from diploid spermatogonia
The proteins encoded by these genes have been shown to function in different cellular compartments and affect distinct stages of acrosome biogenesis such as protein processing in the ER (GBA2, HSP90b1), trafficking of vesicles from the Golgi apparatus (PICK1, GOPC, CSNK2a2, SMAP2), normal fusion of acrosomal vesicles (VPS54, HRB), integrity of acrosomal matrix (ZPBP1/2), and interaction of the acrosome with the acroplaxome (SPACA1) or the nuclear envelope (DPY19L2), amongst others
The study reported here shows that absence of AU040320 protein in mice leads to male infertility due to gross cell morphology abnormalities characterised by mutant spermatozoa displaying a rounded head and no acrosome, features reminiscent of human globozoospermia[9,10]
Summary
Spermatogenesis is a complex developmental process by which mammalian spermatozoa, the male haploid germ cells, are produced from diploid spermatogonia It includes multiple cellular steps and, for simplification, is divided into specific stages (I–XII in mouse) according to the grouping or association of the different cell types detected after cross-section of the seminiferous tubules[1]. These, through a process known as spermiogenesis involving morphologically different and identifiable steps (1–16 in mouse), transform into mature spermatozoa containing a tail (flagellum) and a unique organelle called the acrosome These germinal cell types are arranged in definite associations or stages (I–XII in mouse), containing one or two spermatids, which constitute the cycle of the seminiferous epithelium[2,3,4]. It follows the classic clathrin trafficking pathway (Velayos-Baeza et al, in preparation) and functions as a receptor for the infection of adeno-associated virus into cells[28]
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