Abstract
Male infertility due to abnormal spermatozoa has been reported in both animals and humans, but its pathogenic causes, including genetic abnormalities, remain largely unknown. On the other hand, contraceptive options for men are limited, and a specific, reversible and safe method of male contraception has been a long-standing quest in medicine. Some progress has recently been made in exploring the effects of spermatid-specifical genetic factors in controlling male fertility. A comprehensive search of PubMed for articles and reviews published in English before July 2016 was carried out using the search terms ‘spermiogenesis failure', ‘globozoospermia', ‘spermatid-specific', ‘acrosome', ‘infertile', ‘manchette', ‘sperm connecting piece', ‘sperm annulus', ‘sperm ADAMs', ‘flagellar abnormalities', ‘sperm motility loss', ‘sperm ion exchanger' and ‘contraceptive targets'. Importantly, we have opted to focus on articles regarding spermatid-specific factors. Genetic studies to define the structure and physiology of sperm have shown that spermatozoa appear to be one of the most promising contraceptive targets. Here we summarize how these spermatid-specific factors regulate spermiogenesis and categorize them according to their localization and function from spermatid head to tail (e.g., acrosome, manchette, head-tail conjunction, annulus, principal piece of tail). In addition, we emphatically introduce small-molecule contraceptives, such as BRDT and PPP3CC/PPP3R2, which are currently being developed to target spermatogenic-specific proteins. We suggest that blocking the differentiation of haploid germ cells, which rarely affects early spermatogenic cell types and the testicular microenvironment, is a better choice than spermatogenic-specific proteins. The studies described here provide valuable information regarding the genetic and molecular defects causing male mouse infertility to improve our understanding of the importance of spermatid-specific factors in controlling fertility. Although a male contraceptive ‘pill' is still many years away, research into the production of new small-molecule contraceptives targeting spermatid-specific proteins is the right avenue.
Highlights
(2) Male factor infertility is a complex disorder that affects a large sector of the population; most its etiology and genetic testes remain largely unexplored
Gene ablation in mice has been a powerful tool for identifying spermatid-specific proteins essential for spermiogenesis, which might serve as potential targets of male contraception
(1) What are the spermatid-specific factors required for spermiogenesis and how do they control male fertility in mice? Can they be classified into different groups by their localization and function in spermatids?
Summary
The manchette is a transient skirt-like structure in the elongating spermatid head that assembles concurrently with the elongation and condensation of the spermatid nucleus and growth of the centrosome-derived axoneme.[53]. Ablation of Spata[6] (spermatogenesisassociated 6 gene) completely disrupts formation of the connecting piece, leading to acephalic spermatozoa and male sterility in mice.[87,88] Interaction between SPATA6 and myosin light and heavy chain subunits (e.g., MYL6) strongly suggests that SPATA6 is involved in myosin-based microfilament transport during connecting piece formation.[88] Further identification of spermatid-specific factors that control the connection of the sperm head and tail and mutation screening in human teratozoospermia patients remain to be investigated. Recent studies further suggest that Galntl5deficient mice show male infertility owing to attenuated glycolytic enzymes (e.g., PGK2) required for motility and a patient diagnosed with asthenozoospermia had a mutation in the GALNTL5 gene.[157,158,159]
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