The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon's head to tail

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.

Figure 1

Model illustrating the role of some typical globozoospermia-related proteins in acrosome formation. (a) Globozoospermia is characterized by round-headed spermatozoa that lack an acrosome. (b) PICK1, ATG7, GOPC, VPS54, HRB, SPATA16 and ICA1L facilitate formation of trafficking vesicles from the Golgi apparatus to the acrosome. ZPBP1, CK2α', ACRBP and PCSK4 are proteins of the acrosomal matrix. (c) The absence of Dpy19l2 leads to the destabilization of the junction between the acroplaxome and the nuclear envelope

Figure 2

Model illustrating three typical protein complexes that leech on to manchette microtubules. The manchette is a transient skirt-like structure surrounding the elongating spermatid head and is only present during spermatid elongation. In the KIF3A/MNS1/KBP complex, MNS1 co-localizes and interacts with the KIF3A motor protein and KBP in the manchette. In the HOOK1/RIM-BP3/KIF3B complex, the RIM-BP3 protein physically associates with the manchette-bound protein HOOK1 and KIF3B motor protein. In the MORN3/MEIG1/PACRG/motor complex, the MEIG1 and PACRG form a complex and PACRG then associates with the manchette microtubules through motor protein(s). MEIG1 also interacts with the manchette-expressed protein MORN3. In the SPEM1/UBQLN1/RANBP17 complex, the SPEM1 interacts with UBQLN1 and RANBP17 in the manchette of elongating spermatids. LRGUK1 binds to HOOK2 to regulate manchette function. In the KIF27/FUSED/ODF1 complex, the FUSED interacts with the outer dense fibre protein ODF1 and manchette-expressed kinesin KIF27

Figure 3

Schematic diagram of the myosin-based connecting piece and the septin-based annulus. The sperm head and tail are bridged by the connecting piece (green box), while the annulus (red structure) connects the midpiece and the principal piece of the mammalian sperm flagellum. Through interaction with myosin subunits, many factors (e.g., OAZ3, ODF1 and SPATA6) participate in the myosin-based microfilament formation and/or maintenance, which is responsible for formation of the connecting piece. Oaz3-encoded protein p12 interacts with MYPT3 to modulate the activity of protein phosphatase PP1β and PP1γ2. Linking of ODF1 to microtubules might occur via ODF1/SPAG5/SPAG4 interaction. SPATA6 forms a complex with myosin light and heavy chain subunits (e.g., MYL6) during connecting piece formation. The annulus is a complex of septins (SEPT) 1, 2, 4, 6, 7 and 12. These septin complexes are associated with the cochaperone DNAJB13 and SPAG4 specifically interacts with SEPT12. The CCNYL1/CDK16 complex also determines the structure and function of the annulus through posttranscriptional WNT signalling and GSK-mediated SEPT4 clustering in the epididymis

Figure 4

Models for the contributors and roles of the spermatid-specific ER quality-control system. After sperm are deposited in the female reproductive environment, they become metabolically active and pass through the uterotubal junction (UTJ) into the oviduct. ADAM1a, ADAM2, ADAM3, CLGN, CALR3, ACE, PDILT and PMIS2 are spermatid-specific ER chaperones. Disruption of these genes results in similar phenotypes, including impaired migration through the UTJ and/or impaired sperm-ZP binding. Heterodimerization of ADAMs and correct localization of ADAM3 are the central elements for sperm migrating and fertilizing ability. ADAM3 can regulate the PMIS2 expression directly or indirectly. ACE contributes to the removal of TEX101 and LY6K from mature spermatozoa to guarantee correct localization of ADAM3 on the mature sperm surface. Only knockout of Ly6k does not affect the expression and distribution of ADAM3

Figure 5

Schematic figure summarizing the critical roles of sperm-specific NHEs and CatSper. Upon ejaculation, sperm stored in the male reproductive tract enter the uterine cavity where they experience a natural decrease of pH and HCO₃⁻. Normally, sperm adapt quickly to the environment of the female reproductive tract, particularly via Na⁺/H⁺ exchangers that are localized to the principal piece of of the sperm flagellum. However, in spermNHE-null and Nha1/2-null mice, sperm show attenuated sAC-cAMP signalling and reduced motility, resulting in failure of movement towards the ampulla of the uterine tubes to fertilize eggs. The increase in pHi activates a sperm-specific Ca²⁺ permeable channel complex known as CatSper, which allows an intracellular Ca²⁺ increase and activation of the Ca²⁺/CaM/kinase signalling pathway essential for hyperactivation

Figure 6

Models for the small-molecule male contraceptives. BRDT is a testis-specific contraceptive target, and JQ1 is a BRDT inhibitor that causes a reversible contraceptive effect in male mice. Sperm-specific calcineurin contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). Treatment of mice with calcineurin inhibitors, such as cyclosporine A and FK506, leads to rapid and reversible male infertility. However, side effects need to be taken into consideration