Male infertility is an important issue for human reproductive health and contributes to approximately half of the observed infertility in couples. Frequently, male infertility is associated with multiple morphological defects of the sperm flagella (MMAF), which disrupt its motility. Although some proteins involved in MMAF have been identified, a mechanistic understanding of this phenotype is still lacking. Now, Na Li, Ling Sun and co-workers start to unravel the contribution of the sperm protein FSIP2 to sperm function in mice. To study the effects of FSIP2 dosage alterations, they generate a mouse knock-in of an FSIP2 mutation they have identified in a human MMAF patient (Fsip2-KI) and, in addition, a line overexpressing FSIP2 (Fsip2-OE). Whereas, Fsip2-KI animals are sterile, with sperm that are less viable and motile than those of wild-type mice, Fsip2-OE mice are fertile and display a higher proportion of sperm with elongated flagella. Accordingly, FSIP2 overexpression promotes the expression of flagellar genes and those involved in spermatid development and differentiation. FSIP2 appears to have an additional function in the acrosome, an organelle containing enzymes for penetration of the oocyte, as Fsip2-OE mice express acrosomal genes more strongly and FSIP2 interacts with the acrosomal protein ACVR1. Collectively, these findings provide new mechanistic insight into the function of FSIP2 and its regulation of sperm motility and fertilization.
