Heads or tails? Structural events and molecular mechanisms that promote mammalian sperm acrosomal exocytosis and motility

Abstract

Sperm structure has evolved to be very compact and compartmentalized to enable the motor (the flagellum) to transport the nuclear cargo (the head) to the egg. Furthermore, sperm do not exhibit progressive motility and are not capable of undergoing acrosomal exocytosis immediately following their release into the lumen of the seminiferous tubules, the site of spermatogenesis in the testis. These cells require maturation in the epididymis and female reproductive tract before they become competent for fertilization. Here we review aspects of the structural and molecular mechanisms that promote forward motility, hyperactivated motility, and acrosomal exocytosis. As a result, we favor a model articulated by others that the flagellum senses external signals and communicates with the head by second messengers to affect sperm functions such as acrosomal exocytosis. We hope this conceptual framework will serve to stimulate thinking and experimental investigations concerning the various steps of activating a sperm from a quiescent state to a gamete that is fully competent and committed to fertilization. The three themes of compartmentalization, competence, and commitment are key to an understanding of the molecular mechanisms of sperm activation. Comprehending these processes will have a considerable impact on the management of fertility problems, the development of contraceptive methods, and, potentially, elucidation of analogous processes in other cell systems.

Figure 1

Schematic drawing of a mouse sperm, indicating the physical compartments (head and flagellum) and their respective sub-compartments. Some of the functions or activities discussed in this review are diagrammatically represented below the drawing of the sperm. Guide to structures: acrosome (pink), nucleus (black), mitochondria (green), axoneme (blue), fibrous sheath (red), outer dense fibers (lavender), and cytoplasm (yellow). Also depicted are the compartments within the sperm head (acrosome, nucleus) and flagellum (axoneme, midpiece, principal piece, end piece). Mitochondria in the midpiece compartmentalize oxidative phosphorylation whereas glycolysis is restricted to the fibrous sheath. Examples of proteins localized within in the flagellum are: AK1 (adenylate kinase 1), AK2 (adenylate kinase 2), AKAP 3/4 (A-kinase anchoring protein 3/4), CATSPER 1/4 (cation channel, sperm associated 1/4), GAPDHS (glyceraldehyde phosphate dehydrogenase, spermatogenic), HK1-sc (hexokinase 1, spermatic cell), ODF 1/2 (outer dense protein 1/2), SACY (soluble adenylyl cyclase), SLC9A10 (solute carrier family 9, member 10; sNHE; sperm-specific Na+/H+ exchanger), TUBA (tubulin, alpha), TUBB (tubulin, beta).

Figure 2

Diagram of the activation pathways operative in sperm. This flowchart assimilates many of the pathways described for sperm from mouse and human, and presents the pathways using the mouse nomenclature. The diagram is by no means complete, and not all paths may eventually be shown to be accurate for the mouse. It is presented to serve as a conceptual framework. Question marks (??) indicate three areas that need further experimental investigational support: the role of an anterograde calcium cascade from the tail to the head, the intermediate steps between cAMP and GSK3, and the interaction between SLC9A10 (solute carrier family 9, member 10; sNHE; sperm-specific Na+/H+ exchanger) and SACY (soluble adenylyl cyclase). Other proteins depicted include: ADCY3 (adenylate cyclase 3), CATSPER (cation channel, sperm associated), CFTR (cystic fibrosis transmembrane conductance regulator), GSK3 (glycogen synthase kinase 3), HVCN1 (hydrogen voltage-gated channel; homolog of human Hv1), KCNU1 (potassium channel, subfamily U, member 1; SLO3), RAPGEF3 (Rap guanine nucleotide exchange factor 3; EPAC). For the sake of clarity, not all of the steps in sperm activation are presented.

Figure 3

Speculative model of how the flagellum could serve as a sensory organelle of mammalian sperm and lead to a physiological response such as acrosomal exocytosis. This model assumes that the sperm has undergone all necessary steps of maturation to be competent to respond to an external signal. 1) An extracellular ligand binds to and activates a receptor compartmentalized in the principal piece of the sperm flagellum. 2) As a result of receptor activation, the plasma membrane proton pump becomes activated and the cytoplasm becomes alkalinized. 3) As a result of the intracellular pH increase, KCNU1 is activated, leading to the hyperpolarization of the membrane, and CATSPER channels open, allowing extracellular calcium to enter the sperm. 3) Internal calcium increases throughout principal piece of the sperm, causing a wave that progresses in an anterograde direction toward the sperm head. 4) As the calcium wave progresses, the signal is amplified by the release of calcium from internal stores, such as the redundant nuclear envelope near the head-tail junction. 5) In response to the wave of calcium emanating forward from the flagellum, acrosomal exocytosis progresses in an anterograde direction.