Dynamic Development
CONTENTS

Main Page Dynamic Development

The Foundations of Developmental Biology

Gametogenesis

From Sperm and Egg to Embryo

Genetic Regulation of Development

Organizing the Multicellular Embryo

Generating Cell Diversity


Dynamic Development at a Glance


Learning Resources

Research Resources

The Developmental Biology Journal Club

Developmental Biology Tutorial

Spermatogenesis

Why do developing sperm need their neighbors?

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 very efficient "sperm factories," which produce vast numbers of these elaborate cells.

Germ Cell - Somatic Cell Interactions

Sperm develop in association with specialized somatic cells. We shall examine this relationship in mammals.

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.

(See Browder et al., 1991, Fig. 2.12; Gilbert, 1997, Fig. 22.15; Kalthoff, 1996, Fig.3.7; Shostak, 1991, Fig. 7.6)

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.

Signals Involved in 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 intimate relationship between the germ cells and Sertoli cells involves reciprocal paracrine interactions between these two cell types, and the overall coordination of spermatogenesis is orchestrated by endocrine interactions between the pituitary gland and the somatic cells of the testis.

(See Browder et al., 1991, Fig. 2.14; Shostak, 1991, Fig. 7.20)

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. What does this tell you about the relationship between germ cells and Sertoli cells?

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; also called Clusterin or Apolipoprotein J). 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. SGP-2 is thought to be involved in protecting cells from apoptotic cell death (Clark et al, 1997; Clark and Griswold, 1997; Viard et al, 1999)

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- 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- 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- receptors are expressed in the mammalian testis, suggesting that members of the TGF- 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 (Zhao et al., 1996). The somatic cells in the testis do not appear to be affected.

These results suggest that BMP8 is required for the resumption of male germ-cell proliferation at puberty and the maintenance of the germ cells in the adult.

Sperm Structure

Sperm come in a variety of shapes and sizes. The most elaborate sperm are found in species with internal fertilization.

(See Browder et al., 1991, Fig. 2.3; Shostak, 1991, Fig. 6.1)

The primary components of typical sperm are the nucleus, acrosome and flagellum. We shall now examine mammalian sperm structure in detail.

(See Browder et al., 1991, Figs. 2.4-2.6; Gilbert, 1997, Fig. 4.2; Kalthoff, 1996, Fig. 3.9; Shostak, 1991, Figs. 7.12-7.13; Wolpert et al., 1998, Fig. 12.21)

The apical segment of the acrosome extends past the tip of the nucleus. It often assumes a species-specific shape. In other species, it is small and inconspicuous (e.g., in humans). The acrosome contains hydrolytic enzymes, which are released from the sperm during the acrosome reaction. This occurs in the immediate vicinity of the egg and causes the sperm plasma membrane and the outer acrosomal membrane to vesiculate and be shed, thus releasing the enzymes. We shall discuss the roles of these enzymes in penetration of the egg accessory layers later.

The posterior portion of the acrosome is the equatorial segment, which remains intact during the acrosome reaction and is the site of initial contact between the sperm and egg at fertilization.

The tail contains the motor apparatus of the sperm. It consists of two central microtubules surrounded by 9 microtubule doublets. (This structure is called the axoneme) The arms associated with the outer doublets are composed of dynein. The essential role of dynein in motility is demonstrated by immotile cilia syndrome. Dynein arms can be eliminated from demembranated sperm. Restoration of dynein re-establishes motility. Modified dynein molecules that lack ATPase activity are immotile. What does this tell you about dynein function?

(See Browder et al., 1991, Fig. 2.8; Gilbert, 1997, Fig. 4.3; Kalthoff, 1996, Fig. 18.16; Shostak, 1991, Figs. 2.19, 6.7)

Interactions between the inner microtubules and the radial spokes coordinate the sliding activities of the outer doublets and produce the bending action that propels the sperm.

The outer dense fibers are involved in flagellar flexibility. Absence of outer dense fibers alters flagellar flexibility and results in modified flagellar beat, causing sterility.

(See Browder et al., 1991, Fig. 2.7; Shostak, 1991, Figs. 6.6, 6. )

The sperm tail and head articulate in the neck.

Mitochondria are located in the middle piece. Mitochondria in mammalian sperm are elongated and wrapped around the axoneme. Why would the sperm have such elaborate mitochondria for their small size?

(See Browder et al., 1991, Fig. 2.9; Shostak, 1991, Figs. 6.4-6.6)

We shall now briefly compare primitive sperm from marine and freshwater invertebrates to those of mammals. These sperm are usually characterized by round or conical nuclei and small acrosomes. The midpiece may be small with a few spheroidal mitochondria.

(See Browder et al., 1991, Fig. 2.11; Gilbert, 1997, Fig. 22.17; Kalthoff, 1996, Fig. 4.4; Shostak, 1991, Fig. 6.3)

The acrosome reaction of marine invertebrate sperm involves eversion of a long slender acrosomal process, the tip of which contacts the egg during fertilization. The surface of the acrosomal process is coated with a protein called bindin, which binds the sperm to the egg vitelline envelope.


Learning Objectives

  • Understand the anatomical relationships of cells within the seminiferous tubules.
  • What is the role of intercellular signaling in spermatogenesis?
  • What are the endocrine, paracrine and autocrine signaling molecules that regulate spermatogenesis, and what role does each play?
  • What is BMP8b, and what is its putative role?
  • What are the components of sperm, and how do they function?


Digging Deeper:

Signals Involved in Regulating Spermatogenesis

Additional Topics

Boujrad, N., Hochereau-de Reviers, M.T. and Carreau, S. 1995. Evidence for germ cell control of Sertoli cell function in three models of germ cell depletion in adult rat. Biol. Reprod. 53: 1345-1352.

Elliott, D.J. and Cooke, Howard J. 1997. The molecular genetics of male infertility. BioEssays 19: 801-809.

Grandjean, V., Sage, J., Ranc, F., Cuzin, F. and Rassoulzadegan, M. 1997. Stage-specific signals in germ line differentiation: control of Sertoli cell phagocytic activity by spermatogenic cells. Develop. Biol. 184: 165-174.

Tenniswood, M., Wang, Z., Lakins, J., Morrissey, C., O'Sullivan, J., and Tang, H. 1998. Clusterin in the male reproductive tract. J. Androl. 19:508-16.

Zhu, D., Dix, D.J. and Eddy, E.M. 1997. HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes. Development 124: 3007-3014.


References

Browder, L.W., Erickson, C.A. and Jeffery, W.R. 1991. Developmental Biology. Third edition. Saunders College Pub. Philadelphia.

Clark, A.M. and Griswold, M.D. 1997. Expression of clusterin/sulfated glycoprotein-2 under conditionsof heat stress in rat Sertoli cells and a mouse Sertoli cell line. J. Androl. 18:257-63.

Clark A.M., Maguire, S.M., and Griswold, M.D. 1997. Accumulation of clusterin/sulfated glycoprotein-2 in degenerating pachytene spermatocytes of adult rats treated with methoxyacetic acid. Biol. Reprod. 57: 837-46.

Gilbert, S.F. 1997. Developmental Biology. Fifth Edition. Sinauer. Sunderland, MA.

Kalthoff, K. 1996. Analysis of Biological Development. McGraw-Hill. New York.

Shostak, S. 1991. Embryology. An Introduction to Developmental Biology. HarperCollins. New York.

Viard, I., Wehrli, P., Jornot, L., Bullani, R., Vechietti, J.L., Schifferli, J.A., Tschopp, J., And French, L.E. 1999. J. Invest. Dermatol. 112:290-6.

Wolpert, L., Beddington, R., Brockes, J., Jessell, T., Lawrence, P. and Meyerowitz, E. 1998. Principles of Development. Current Biology. London.

Zhao, G.-Q., Deng, K., Labosky, P.A., Liaw, L. and Hogan, B.L.M. 1996. The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse. Genes & Dev. 10: 1657-1669

 


Dynamic Development at a Glance
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Leon Browder & Laurie Iten (Ed.) Dynamic Development
Last revised Thursday, June 11, 1998