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.
Highlights
Male InfertilityBetween 2% and 12% of couples globally are affected by low fertility, and the cause in approximately half of these cases can be traced to the men [1]
Several nuclear or nuclear membrane-related proteins were identified as SEPT12 interactors through the yeast 2-hybrid system; one of these interactors is NDC1 [17]
SEPT12 mutations in human and mice spermatozoa were demonstrated to caIunsoeutrepraretovzioouosspsteurmdyi,aSE(eP.Tg1.,2 nmuuctlaetairondsainmhaguem, apnraenmdamtuircee scpherrommaotsoozmoaawl ecroenddeemnsoantsiotrna,teadntdo acbanuosermtearlatmozooropshpoelromgiieas(eo.fg.s,pneurcmleahredadams agned, ptarielms)a[t1u3r–e1c5h,2ro5m]. oNsDomCa1l wcoansdiednesnatifoiend, aansdaabSnEoPrTm1a2l imntoerrpahctoolrogtihersooufgshpetrhme hyeeaadsst a2n-hdytabirlisd) [s1y3s–t1e5m,25b]y
Summary
Between 2% and 12% of couples globally are affected by low fertility, and the cause in approximately half of these cases can be traced to the men [1]. Intracytoplasmic sperm injection (ICSI) created a breakthrough in assisted reproduction, many infertile cases are still unable to achieve paternity, even when combined with testicular sperm extraction. The sperm-related causes of ICSI failure include immotile or immature sperm, sperm with structural defects, the absence of sperm, and sperm with premature chromosomal condensation or DNA damage [3]. SEPTs participate in membrane compartmentalization, cytoskeletal remodeling, cell polarity, and spermatogenesis through interaction with cytoskeletal proteins [5]. Sperm from SEPT12-mutated mice exhibited unique morphological defects (e.g., immature sperm head, bent tail, premature chromosomal condensation, and nuclear damage) [13]. Several nuclear or nuclear membrane-related proteins were identified as SEPT12 interactors through the yeast 2-hybrid system; one of these interactors is NDC1 [17]
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