The Expression Level of Septin12 Is Critical for Spermiogenesis

Abstract

Septins belong to a family of polymerizing GTP-binding proteins that are required for many cellular functions, such as membrane compartmentalization, vesicular trafficking, mitosis, and cytoskeletal remodeling. One family member, septin12, is expressed specifically in the testis. In this study, we found septin12 expressed in multiple subcellular compartments during terminal differentiation of mouse germ cells. In humans, the testicular tissues of men with either hypospermatogenesis or maturation arrest had lower levels of SEPTIN12 transcripts than normal men. In addition, increased numbers of spermatozoa with abnormal head, neck, and tail morphologies lacked SEPT12 immunostaining signals, as compared with normal spermatozoa. To elucidate the role of septin12, we generated 129 embryonic stem cells containing a septin12 mutant allele with a deletion in the exons that encode the N-terminal GTP-binding domain. Most chimeras derived from the targeted embryonic stem cells were infertile, and the few fertile chimeras only produced offspring with a C57BL/6 background. Semen analysis of the infertile chimeras showed a decreased sperm count, decreased sperm motility, and spermatozoa with defects involving all subcellular compartments. The testicular phenotypes included maturation arrest of germ cells at the spermatid stage, sloughing of round spermatids, and increased apoptosis of germ cells. Electron microscopic examination of spermatozoa showed misshapen nuclei, disorganized mitochondria, and broken acrosomes. Our data indicate that Septin12 expression levels are critical for mammalian spermiogenesis.

The expression pattern of SEPT7 correlates with sperm morphology

“…The expression pattern of SEPT7 was reminiscent of that observed for SEPT12 in the post-meiotic germ cell [11]. The expression pattern suggested that SEPT7/SEPT12 may regulate the formation of all four subcellular compartments (i.e., acrosome, head, midpiece, and tail) jointly during spermiogenesis.…”

“…We also found a significant loss of SEPT12 in sperm samples from men with asthenozoospermia. Our results indicate that SEPT12 plays critical roles during terminal differentiation of male germ cells in both mice and humans [11].…”

“…This expression pattern suggests that SEPT7 may be involved in the regulation of the formation of the midpiece and annulus. Previous studies showed that SEPT1/4/6/7/12 are located at the sperm annulus and that this septin-based organization is a requisite for the structural and functional integrity of sperm [7,8,11,23]. Other proteins located at the mouse sperm annulus include DNAJB13 [24] and testis anion transporter 1 (TAT1) [25].…”

“…Other proteins located at the mouse sperm annulus include DNAJB13 [24] and testis anion transporter 1 (TAT1) [25]. In the mouse, gene targeting of Septin4, Septin12, and Tat1 lead to abnormal mitochondrial organization and tail defects [6,7,11,25]. In humans, absence of the annulus is associated with abnormal mitochondrial organization in poor-motility sperm [9].…”

Human male infertility and its genetic causes

“…The Sept12 chimeric mice also harbored significant DNA damage in their spermatozoa. The embryos that were generated by in vitro fertilization and ICSI failed to develop beyond the morula stage 58, 59. In 2012, two missense SEPT12 (16p13.3) mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, were reported in infertile men 60.…”