Cortical Organization by the Septin Cytoskeleton Is Essential for Structural and Mechanical Integrity of Mammalian Spermatozoa

Abstract

Septins are polymerizing GTP binding proteins required for cortical organization during cytokinesis and other cellular processes. A mammalian septin gene Sept4 is expressed mainly in postmitotic neural cells and postmeiotic male germ cells. In mouse and human spermatozoa, SEPT4 and other septins are found in the annulus, a cortical ring which separates the middle and principal pieces. Sept4-/- male mice are sterile due to defective morphology and motility of the sperm flagellum. In Sept4 null spermatozoa, the annulus is replaced by a fragile segment lacking cortical material, beneath which kinesin-mediated intraflagellar transport stalls. The sterility is rescued by injection of sperm into oocytes, demonstrating that each Sept4 null spermatozoon carries an intact haploid genome. The annulus/septin ring is also disorganized in spermatozoa from a subset of human patients with asthenospermia syndrome. Thus, cortical organization based on circular assembly of the septin cytoskeleton is essential for the structural and mechanical integrity of mammalian spermatozoa.

The expression pattern of SEPT7 correlates with sperm morphology

“…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].…”

“…The surplus cytoplasm is completely removed around the time of ejaculation via an unidentified mechanism [33]. Considering that Septin4 knockout mice also exhibit increased rates of immature sperm [7,8], SEPT4/7 may participate jointly in the regulation of the removal of the residual cytoplasm during sperm maturation.…”

“…There is increasing evidence of the involvement of septins in the pathogenesis of various human diseases, including neoplasia, neurodegenerative conditions, infection, and infertility [1,[6][7][8]. Among the 14 septin family members, SEPT4 and SEPT12 play important roles in the differentiation of postmeiotic germ cells.…”

“…During spermatogenesis, SEPT4 is essential for the maintenance of proper mitochondrial architecture and for the establishment of the annulus. Septin4 null mice are viable; however, males are sterile because they produce immotile sperm with a defective annulus [7,8]. In humans, disorganized annulus/SEPTIN rings were identified in a subset of patients with asthenozoospermia [9,10].…”

“…SEPT7 is critical for spine morphogenesis and dendrite development in neurons [12]. SEPT7 is also one of the structural constituents of the annulus of human and mouse sperm [8]. A terato-asthenozoospermic patient exhibited the absence of an annulus in 97% of his ejaculated spermatozoa, in which normal SEPT4/7 signals at the annulus were also lacking.…”