Studies on the Function of the Annulus of the Sperm Tail
The annulus on the sperm tail is critical for sperm function; Council research on the annulus may lead to the development of a novel, reversible male contraceptive
During spermatogenesis a round spermatogonium is transformed into a highly polarized, exceedingly streamlined spermatazoon that then must not only exist in several different environments of the male reproductive tract but in various environments of the female reproductive tract as well. Sperm must alter their function as they travel and, when they encounter the egg, undergo a series of modifications so fertilization can occur.
One of the amazing feats of this process is that the sperm accomplish these modifications and alterations in function without generating new proteins. Most somatic cells change their function by altering the complement of proteins made. Sperm, however, do not have this option as they jettison their bulky synthetic machinery in one of the final stages of development to produce their sleek streamlined appearance. Sperm appear to compensate for their inability to synthesize new proteins by rearranging the distribution of their existing proteins at specific times thereby allowing new permutations of interaction that result in new biochemical reactions and modified function.
In order for such a system to work sperm must have three basic components: (1) they must have a means of initially segregating their proteins thus producing a polarized cell; (2) they must have barriers (either physical structures or biophysical forces) that maintain these protein domains; and (3) they require a mechanism of transiently allowing redistribution of certain proteins from one domain to another. The most-studied proteins of this phenomenon are membrane-bound proteins, which will serve as the models for this discussion, but similar mechanisms may exist for cytoplasmic proteins as well. This project centers on the partitioning that goes on in the tail with the focus on the organelle—the annulus—that separates the midpiece domain and principal-piece domain.
Until recently, very little was known about the annulus other than it is a ring-shaped structure at the distal end of the midpiece determining the junction between the midpiece and principal piece of the tail (Figure 1). The molecular composition of the annulus as well as its biogenesis were unknown. Recently, Population Council researchers and others have shown that the annulus is composed of septin proteins that are known to generate ringed structures in other cells.
The annulus has been hypothesized to act as a diffusion barrier between the midpiece and principal-piece membrane domains, and to serve as a stabilizing structure for tail rigidity by securing to it the mictochondrial sheath covering the midpiece and the fibrous sheath covering the principal piece of the tail. Testing these hypotheses, however, has been limited by the fact that the composition of this organelle was unknown and specific probes to it were not available. With the discovery that the annulus is a septin structure—which was revealed when knockout mice to the septin 4 family member were found to be missing the annulus in sperm (Figure 2)—researchers can finally test these hypotheses.
Sperm from the septin 4 knockout mice had a variety of problems in addition to missing the annulus: they could not swim; they had a malfunction in the removal of their cytoplasmic droplets; their tails bent back 180 degrees at the site where the annulus would have been (Figure 3); and they were unable to undergo capacitation—a process necessary in fertilization. Using these knockout mice, Council researchers can investigate the various functions of the annulus and study the causes underlying the reasons sperm lacking the septin 4 gene have such an array of anomalies.
Likewise, the fact that a single gene deletion profoundly affects the sperm suggests that the proteins normally made by this gene are potential targets for the development of novel reversible male contraceptives. Contraceptive approaches that target halting the production of sperm work by manipulating testosterone levels, which can result in unwanted side effects, but tweaking a specific protein on a sperm to disable it might inhibit fertility without negative side effects. Furthermore, the knowledge gained from these studies will in turn continue to advance medicine’s understanding of human male infertility and potentially improve the fertility and quality of sperm in infertile men.
The Sept4 septin locus is required for sperm terminal differentiation in mice (abstract) (PDF)
Kissel,Holger; Georgescu,Maria-Magdalena; Larisch,Sarit; Manova,Katia; Hunnicutt,Gary R.; Steller,Hermann
Developmental Cell 8(3): 353-364
Publication date: 2005
Location: United States
Reproductive health biomedical research
Duration: 1/2003 - ongoing
Angela Klaus (American Museum of Natural History)
Holger Kissel (The Rockefeller University)
US National Institutes of Health