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The Foundations of Developmental
From Sperm and Egg to Embryo
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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
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
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
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
(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 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
(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
(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,
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
- Understand the anatomical relationships of cells within the seminiferous
- 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?
Signals Involved in Regulating Spermatogenesis
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.
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.
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.
Browder, L.W., Erickson, C.A. and Jeffery, W.R. 1991. Developmental
Biology. Third edition. Saunders College Pub. Philadelphia.
Gilbert, S.F. 1997. Developmental Biology. Fifth Edition. Sinauer.
Kalthoff, K. 1996. Analysis of Biological Development. McGraw-Hill.
Shostak, S. 1991. Embryology. An Introduction to Developmental Biology.
HarperCollins. New York.
Wolpert, L., Beddington, R., Brockes, J., Jessell, T., Lawrence, P. and
Meyerowitz, E. 1998. Principles of Development. Current Biology.
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