Spata6 is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Abstract

"Pinhead sperm," or "acephalic sperm," a type of human teratozoospermia, refers to the condition in which ejaculate contains mostly sperm flagella without heads. Family clustering and homogeneity of this syndrome suggests a genetic basis, but the causative genes remain largely unknown. Here we report that Spata6, an evolutionarily conserved testis-specific gene, encodes a protein required for formation of the segmented columns and the capitulum, two major structures of the sperm connecting piece essential for linking the developing flagellum to the head during late spermiogenesis. Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Our proteomic analyses reveal that SPATA6 is involved in myosin-based microfilament transport through interaction with myosin subunits (e.g., MYL6).M ale gametes-spermatozoa-are produced in the testis through a process termed spermatogenesis, which can be divided into three phases: mitotic, meiotic, and haploid (1). In the mitotic phase, spermatogonial stem cells proliferate and differentiate into spermatogonia, which subsequently enter the meiotic phase and become spermatocytes. Spermatocytes undergo crossover, followed by two consecutive meiotic cell divisions to produce haploid spermatids. Spermatids then undergo a multistep differentiation process, also called spermiogenesis, to form spermatozoa. Severe disruptions in either the mitotic or the meiotic phase tend to cause azoospermia, whereas spermiogenic defects often lead to reduced sperm counts, aberrant sperm motility, and deformed spermatozoa, a condition termed oligoasthenoteratozoospermia (OAT) in humans (2, 3).OAT accounts for a significant proportion of male idiopathic infertility cases (2, 4). Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14). Extensive ultrastructral studies on humans and animals with acephalic spermatozoa suggest that this condition results from defects in formation of the connecting piece of spermatozoa during late spermiogenesis, including failure for the proximal centrioles to attach normally to the caudal portion of the sperm nuclei, leading to abnormal head-midpiece alignment, or a nuclear defect that interferes with formation of the implantation fossa, the normal lodging site for the sperm proximal centriole (16). Aberrant formation of the connecting piece leads to independent development of the sperm heads and flagella, and eventually these structures become separated within the seminiferous tubules or during their transition through the seminal tract as a consequence of increased instability of the head-midpiece junction (16,18)....

SPATC 1L maintains the integrity of the sperm head‐tail junction

“…However, the roles of PKA in spermatogenic cell centrioles and flagellar basal bodies during sperm development have not been elucidated, despite the fact that PKA is known for its roles in sperm capacitation [21]. Acephaly in sperm, an abnormality that represents a type of teratozoospermia, is associated with some of the male infertility cases [12] and has been linked to loss of function of several genes [31][32][33][34][35][36]. It is well known that PKA is activated by cAMP binding to the R subunit.…”

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

“…Ablation of Spata6 (spermatogenesis-associated 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.…”

Genome-wide association for testis weight in the diversity outbred mouse population

“…Both Spata6 and its human ortholog SPATA6 are known to be expressed exclusively in the testis in adults (Oh et al 2003; Huo et al 2015). In addition, it has been reported that SPATA6 is required for assembly of the sperm connecting piece and tight head-tail conjunction, and that inactivation of Spata6 causes acephalic spermatozoa and sterility in male mice (Yuan et al 2015). While Spata6 has not been previously identified as a candidate gene for testis weight variation, it is worth noting that Spata6 lies just outside the proximal boundary of a QTL for testis weight reported by Bolor et al (2006).…”