SEPT12–NDC1 Complexes Are Required for Mammalian Spermiogenesis

Abstract

Male factor infertility accounts for approximately 50 percent of infertile couples. The male factor-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile sperm, immature sperm, abnormally structured sperm, and sperm with nuclear damage. Our knockout and knock-in mice models demonstrated that SEPTIN12 (SEPT12) is vital for the formation of sperm morphological characteristics during spermiogenesis. In the clinical aspect, mutated SEPT12 in men results in oligozoospermia or teratozoospermia or both. Sperm with mutated SEPT12 revealed abnormal head and tail structures, decreased chromosomal condensation, and nuclear damage. Furthermore, several nuclear or nuclear membrane-related proteins have been identified as SEPT12 interactors through the yeast 2-hybrid system, including NDC1 transmembrane nucleoporin (NDC1). NDC1 is a major nuclear pore protein, and is critical for nuclear pore complex assembly and nuclear morphology maintenance in mammalian cells. Mutated NDC1 cause gametogenesis defects and skeletal malformations in mice, which were detected spontaneously in the A/J strain. In this study, we characterized the functional effects of SEPT12–NDC1 complexes during mammalian spermiogenesis. In mature human spermatozoa, SEPT12 and NDC1 are majorly colocalized in the centrosome regions; however, NDC1 is only slightly co-expressed with SEPT12 at the annulus of the sperm tail. In addition, SEPT12 interacts with NDC1 in the male germ cell line through coimmunoprecipitation. During murine spermiogenesis, we observed that NDC1 was located at the nuclear membrane of spermatids and at the necks of mature spermatozoa. In male germ cell lines, NDC1 overexpression restricted the localization of SEPT12 to the nucleus and repressed the filament formation of SEPT12. In mice sperm with mutated SEPT12, NDC1 dispersed around the manchette region of the sperm head and annulus, compared with concentrating at the sperm neck of wild-type sperm. These results indicate that SEPT12–NDC1 complexes are involved in mammalian spermiogenesis.

Gene set enrichment analysis and meta-analysis to identify six key genes regulating and controlling the prognosis of esophageal squamous cell carcinoma

“…NDC1-mediated ALADIN localization of the nuclear pore complexes is critical for selective nuclear protein introduction (29). The research on NDC1 and Nup107 is mostly about the effects of these two genes on sperm formation and infertility (30,31). The central domain of Nup107 interferes with Apaf-1 nuclear translocation during genotoxic stress, leading to Chk-1 activation, and a significant reduction in cell cycle arrest (32).…”

Role of Nucleoporins and Transport Receptors in Cell Differentiation

“…However, further studies are required to determine the effects of Nup210 binding to calcium muscle differentiation (Gomez-Cavazos and Hetzer, 2015). NDC-1 interacts with SEPTIN to form a complex that is co-expressed at the manchette and neck region of sperm during terminal differentiation in mammalian spermiogenesis (Lai et al, 2016).…”

Single‐nucleotide polymorphism c.474G>A in the SEPT12 gene is a predisposing factor in male infertility

“…SEPT12 dysfunction or a reduction in its expression is affiliated with perturbation of sperm head shaping and tail elongation by affecting the organization of α‐ and β‐tubulins (Kuo et al, ). Besides, SEPT12 forms complexes with sperm‐associated antigen 4 (SPAG4) and NDC1 proteins implicated in maintaining the integrity of the nuclear envelope and facilitation of precise sperm head and tail formation respectively (Lai et al, ; Yeh et al, ). Current investigations have been revealed that SEPT12 +/− chimeric mice are sterile due to drastic sperm pathologies, including immotility, defects of the annulus, round head, bent tail, acrosome break, and disrupted mitochondrial architecture (Lin et al, ; Lin, Kuo, Chiang, & Kuo, ).…”