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Submitted by Dr. Hesham Al-Inany, M.D. Lecturer, Gynaecology & Obstetrics
dept. Kasr El-Aini hospital, Cairo University, Egypt.
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The nature of the sperm-egg interaction during fertilization leads to the
sharing of membrane components.
The sperm and eggs arise from primordial germ cells (PGCs). These cells
appear shortly after implantation when the embryo is composed of only a
few thousand cells. Thus, PGC determination is one of the earliest events
in embryogenesis. These cells arise very early in humans at about 4 weeks
of gestation in the yolk sac endoderm and are easily recognized because
they contain large amounts of the enzyme alkaline phosphatase.
The PGCs migrate by ameboid movement into the dorsal mesentery of the
embryo and then laterally into the genital ridges that are near the site
of the future kidneys. During migration, the PGCs divide to yield several
thousands cells. At the time of their arrival in the genital ridge, the
female and male embryos are morphologically indistinguishable. However,
shortly after the PGCs take up residence in the genital ridge, at about
6 weeks of gestation in humans, a difference in the sexes becomes apparent:
in females the genital ridge remains unchanged in morphology, whereas the
male gonad develops sex cords.
In males, the PGCs become diploid spermatogonia . These cells divide
by mitosis until puberty whereupon some of the spermatogonia become committed
to meiosis. However, diploid spermatogonia persist throughout life and serve
as a continous stem cell population.
The spermatogonia committed to meiosis become primary spermatocytes, and
it is in these cells that genetic crossing over occurs. After completion
of meiosis, the diploid spermatids develop a tail and a condensed head.
During this process of spermiogenesis, the spermatids move toward the lumen
of the testicular seminiferous tubule and are released into the lumen.
In females, the pattern of differentiation is markedly different. Shortly
after arrival in the genital ridge, the female PGCs cease dividing and become
primary oocytes. These cells replicate their DNA for the first meiotic division
and then undergo crossing over. While still in the prophase of the first
meiotic division and with the points of chromosome synapsis still visible,
these cells then become arrested.
While eggs may remain in this state until puberty when menarche occurs,
the majority resume meiosis I at varying times (in utero, infancy, prepuberty)
only to be lost short of ovulation in atresia and resolution.
After menarche, in each menstrual cycle a few follicles will develop
and proceed toward ovulation. During follicular growth, eggs move to metaphase
of the first meiotic division. At ovulation, the first meiotic division
is completed, the first polar body is released, and the eggs proceed to
metaphase of the second meiotic division. Here they remain until fertilized,
and it is only after fertilization that the egg completes meiosis and releases
a second polar body.
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The pattern of gene regulation during gametogenesis is among the most
unusual of all cell types. In the male, a remarkable regulatory event occurs
in the primary spermatocyte. In this diploid XY cell, the only functional
X chromosome undergoes inactivation in a manner indistinguishable from lyonization
of the supernumerary X in XX female somatic cells.
Thus, the primary spermatocyte is the only diploid cell in the mammals
without an active X chromosome. When an additional X chromosome is present
as in klinefelter's syndrome (XXY), only one of the two X chromosomes is
inactivated, and meiosis does not occur. This accounts for sterility in
The developing spermatozoon compensate for the total absence of genetic
activity from its X chromosome probably through messenger RNA (mRNA) storage.
The X-linked genes are transcribed, but their mRMA is stored for use after
X inactivation. Another compensatory mechanism has been the evolution of
autosomal genes encoding enzymes similar to those encoded by X-linked genes.
After meiosis in males, the entire haploid genome must be packaged into
the sperm head for transport to the egg. Thus, during spermatogenesis very
little gene transcription occurs, and the DNA becomes complexed with proteins
that bind very tightly. A few genes do function even after meiosis, and
the isolation and characterization of this highly specialized subset of
genes are very active areas of research.
After leaving the testis, a sperm is an elongated flagellated cell with
numerous well developed mitochondria that supply energy for movement and
with a condensed nucleus covered by the acrosome, a large structure containing
a variety of enzymes.
However, at this stage sperm are not still motile and cannot fertilize
eggs. They first pass through the epididymis where further modifications
of the head and tail take place and where proteins synthesized by epididymal
cells are applied to the sperm surface. Maturation events in the epididymis
are androgen dependent.
By the time the sperm reach the distal cauda epididymis, they are prepared
for entry into the female reproductive tract where they undergo further
modifications prior to fertilization.
After ejaculation, the sperm is still not capable of fertilization. They
first must undergo capacitation, a poorly understood process that leads
to a characteristic activated pattern of motility. Capacitation involves
removal of proteins that coat the sperm. Capacitation time varies among
species but in general occurs within a few hours of ejaculation.
After capacitation, the sperm undergoes the acrosome reaction (AR). The
acrosomal reaction leads to the release of the hydrolytic enzymes in the
acrosome into the environment and exposure of the inner acrosomal membrane
of the sperm.
The AR serves two main purposes:
- Release of enzymes as hyaluronidase and protease which aid dissolution
of investments surrounding the oocyte. After ovulation the oocyte is surrounded
with the cumulus oophorus, a cloud of cumulus cells held together with
hyaluronic acid. Inside the cumulus is the zona pellucida (ZP), a glycoprotein
shell around the egg. This structure must be traversed for fetilization
The acrosomal protease acrosin can dissolve the ZP, and some of this enzyme
remains associated with the inner acrosomal membrane after the AR. Presumably,
this remaining enzyme is brought into contact with the ZP at the time
of sperm binding. Then, through the force of sperm motility and digestion
by acrosin, the sperm penetrates the zona and gains access to the oocyte
- Expose proteins on the inner acrosomal membrane which mediates sperm
binding to the oocyte surface. The egg surface has receptors specific
for sperm proteins.
In many species, initial binding to the zona occurs prior to the AR. The
zona pellucida protein (ZP3) then induces the AR and the sperm penetrates
to reach the perivitelline space. Thus, sperm which undergo the AR spontaneously
prior to contact with zona cannot bind to it or penetrate.
The precise sequence of events leading to sperm-egg fusion varies among
species and is not entirely known for humans. In some species, sperm apparently
bind to the ZP before undergoing the AR, while in others the AR is completed
prior to zona binding.
One consistent features of the fusion process is the probable role of
sperm motility. Sperm do not swim to the site of fertilization but rather
are brought there by fluid convection in the female tract. In all mammals,
motility probably serves to aid the sperm in passing through the cumulus
As in spermatogenesis, gene regulation in oogenesis is highly unusual.
Whereas the spermatocyte is the only diploid cell without an active X, the
premeiotic oocyte is the only diploid cell in which more than one X chromosome
At this stage of oogenesis, the inactive X chromosome is reactivated. Why
the second X chromosome is reactivated is not clear, but failure to do so
is severely deleterious to oogenesis. In humans with Turner's syndrome (XO),
there exists only one X chromosome, and these individual are sterile.
Fetal oocytes are arrested in the first prophase of meiosis shortly after
chromsome crossing over. At this time, the nuclear membrane is still visible
and is called germinal vesicle.
Some oocytes remain at this "dictyate" stage until the beginning of the
menstrual cycle. With each cycle, a cohort of these follicles begins to
develop and resume meiosis. One dominant follicle complete maturation and
release an egg. At ovulation, the oocyte completes the first meiotic division
and extrudes the first polar body and proceeds to metaphase of the second
meiotic division, where it again arrests pending arrival of the sperm only
after activation by the process of sperm-egg fusion meiosis is completed
with extrusion of the second polar body and formation of a female pronucleus.
The nature of the sperm-egg interaction that constitutes the fertilization
process is poorly understood but leads to the sharing of membrane components
of the sperm and egg. At this time, the egg becomes "activated". The activation
process leads to completion of meiosis, extrusion of the second polar body
and the development of a block to polyspermia; preventing supernumerary
sperm from entering the egg.
The block to polyspermia involves release of cortical granules - vesicles
which underlie the plasma membrane prior to activation. Release of the cortical
granule contents into the perivetilline space results in an alternation
of the character of the ZP such that further sperm binding is blocked (Gordon,
The species specificity of the fertilization process is provided by the
ZP and the oocyte membrane. It is rare for sperm of heterologous species
to pass through the zona. However, once the ZP is removed, some oocytes
such as those of the hamster, are penetrable by sperm from several other
mammals, including man (Yanagimachi, 1981).
After sperm entry, both the oocyte and sperm haploid genomes decondense
and appear as membrane-bound pronuclei-spheric bodies in the ooplasm. Sperm-specific
proteins are removed from the DNA , and replication of the female and male
Over the next several hours the pronuclei swell and move toward the center
of the cell. As the time for the first cleavage division approaches, the
pronuclear membranes break down, and the chromosomes line up on the first
mitotic spindle (Yanagimachi, 1981).
In human, the first cleavage division usually occurs within 40 hours. The
four cell stage is reached by 50 hours, and the eight-cell stage occurs
by 70 hours after fertilization The morula stage (60-150 cells) develops
3 days postfertilization.
Cleavage Cleavage is the process of early mitotic
cell divisons, which progressively reduce cell size. During cleavage, the
total embryonic mass remains relatively constant. When the embryo has about
16 cells, its individual cells begin to adhere to one
another, and it coalesces into a morula (Latin for mulberry) shape.
Blastocyst Formation: A cavity forms in the morula when it enters the
uterus.This cavitation is an important transition from homogeneous cells
to differentiated cell function. This new structure is called a blastocyst.
The blastocyst consists of an outer layer, the trophoblast, and an inner
cluster of cells, the inner cell mass. Continued expansion of the blastocyst
cavity eventually ruptures the protective zona pellucida (shell) surrounding
the morula. Before the morula makes contact with the uterine
wall, the zona pellucida will be shed.
Implantation is the process in which the blastocyst attaches to and penetrates
into the uterine wall. Upon contact with the uterine lining (the endometrium),
newly defined trophoblast cells begin an invasive activity that gives the
embryo access to the deeper layers of the uterine wall. The implanting trophoblast
cells differentiate into two new cell types syncytiotrophoblasts and cytotrophoblasts.
Syncytiotrophoblast cells grow without cell division throughout implantation,
becoming large, multinucleate cells, or syncytia (meaning fused cells) Cytotrophoblasts,
remain individually distinct, mononucleated cells that invade deeper into
the uterine wall than the syncytiotrophoblasts.
(Quoted from Kase, principles and practice of clinical