Spermatogenesis

Sperm are among the most highly specialized cell types ever described. Such specialization is designed to get the sperm to the egg and to fuse with it. The testes are sperm factories, which produce vast numbers of these elaborate cells.

Germ Cell - Somatic Cell Interactions

Sperm develop in association with specialized somatic cells. Mammalian testes contain numerous seminiferous tubules. Sertoli cells are radially distributed around the circumference of the seminiferous tubules. Spermatogonia are located between the Sertoli cells and the basal lamina. As their progeny undergo meiosis and spermiogenesis (differentiation), they are translocated in groups around the circumference of the seminal tubule toward the lumen. Thus, one sees circumferential zones of more advanced cells inside zones of less advanced cells.

This translocation is mediated by the Sertoli cells. When the differentiated spermatozoa reach the tips of the Sertoli cells, they are released into the lumen of the tubule. Tight junctions are formed between adjacent Sertoli cells, producing a diffusion barrier, allowing the Sertoli cells to regulate the environment that bathes the germ cells.

Regulating Spermatogenesis

The coordination of most developmental processes requires a system of extracellular signals to control cellular survival and proliferation, specification of cell fate, patterning and promotion of cell differentiation. Signaling mechanisms require a signal source, a signal reception system and an intracellular signal response system. Signals that originate from a distance and are distributed via the circulation are called endocrine signals or hormones. Signals coming from nearby cells are called paracrine signals. Cells can also signal themselves; such signals are autocrine signals. These various kinds of signals help to insure that development occurs in an orderly way.The major players that regulate mammalian spermatogenesis are:Androgens (e.g., testosterone), which are secreted by the Leydig (interstitial) cells, which are located in the connective tissue between the seminiferous tubules.Luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are released from the pituitary under the control of gonadotropin-releasing hormone (GnRH), from the hypothalamus. Androgens in the circulation cause a reduction in the production of LH under a classical feedback-inhibition mechanism. Germ cells lack FSH receptors, but Sertoli cells have them. One effect of FSH on Sertoli cells is to cause them to secrete androgen-binding protein, which binds to androgens and may facilitate their direct effects on germ cell differentiation. Growth Factors. Growth factors are proteins that bind to receptors in the surface of target cells and either stimulate cell division or alter cell fate.Sertoli cells produce a number of growth factors of significance. One is seminiferous growth factor (SGF), which stimulates somatic cell proliferation and blood vessel production in the testis during fetal and postnatal development. In the adult, Sertoli cells respond to their own production of SGF by producing sulfated glycoprotein-2 (SGP-2). This is an autocrine interaction. What mechanism would allow a Sertoli cell to respond to its own secretory product? SGP-2 is the major secretory product of adult Sertoli cells. It, in turn, binds to the membranes of spermatozoa. This is a paracrine interaction.Another growth factor is inhibin, which is released from Sertoli cells into the circulation and functions to suppress the secretion of FSH from the pituitary . Circulating levels of FSH, in turn, regulate inhibin production, indicating that a classical negative-feedback mechanism operates. Inhibin is a member of the TGF-ß superfamily of growth factors. Inhibins are heterodimeric proteins (i.e., they are composed of two different polypeptides) of an alpha chain and a beta chain. A related growth factor is activin, which consists of two beta chains. (Activin has been implicated in embryonic induction.)Another category of TGF-ß molecules of significance for spermatogenesis is the bone morphogenetic protein (BMP) family. This is a diverse family of secreted signaling molecules, whose members are involved in controlling a variety of developmental processes. TGF-ß receptors are expressed in the mammalian testis, suggesting that members of the TGF-ß family of signaling molecules play a role in spermatogenesis. At least one member of this family, BMP8b, which is produced within the germ cells themselves, is essential for spermatogenesis in mice. The requirement for BMP8b for spermatogenesis has been demonstrated by the gene knock-out technique. This technique enables investigators to selectively eliminate specific genes and assess the consequences. Testes of the mutant mice show two distinct effects. During early puberty, the germ cells show either a failure or reduced capacity for proliferation and delayed differentiation. In adults, the spermatocytes have a significantly elevated incidence of programmed cell death (apoptosis), which leads to depletion of the germ cells and, consequently, sterility.