Genetherapy

Archive for the ‘Embryology’ Category

The 6th International Symposium on Diabetes & Pregnancy (DIP) Salzburg, Austria March 24-26, 2011

The field of diabetes and pregnancy has come of age. From the conception of the terminology ‘gestational diabetes’ and ‘diabetes in pregnancy’ to the creation of an entire subspecialty, this Symposium documents the ‘gestation’ of the field.
This Symposium not only documents the past 80+ years of progress in the field of diabetes and pregnancy, but also presents the most up-to-date tools, techniques and management protocols to ensure the optimal outcome of pregnancies complicated by diabetes. In addition, the areas that remain controversial, such as screening and diagnosis, will be discussed in detail to enable participants to come to an opinion while waiting for the evidence to validate many of the expert opinions presented.
The latest theories and literature on the immunology of Type 1 diabetes will also be included, giving us hope that the near future holds the answers to prevention of this disease. Until there is a cure for diabetes, we must continually take on the weight of astutely diagnosing diabetes and treating all pregnant women who are at risk of an untoward outcome of pregnancy.
The faculty is comprised of renowned professionals and practitioners, who will present based on evidence as well as clinical experience.
In addition, this Symposium provides an international approach to enhancing the quality of care for women with diabetes in pregnancy, and answers for the clinician to enable delivery of optimal care for all pregnancies complicated by diabetes.

(More? UNSW Embryology - Abnormal Development – Maternal Diabetes | Endocrine Development – Pancreas)

A new report by the Australian Institute of Health and Welfare – Ovarian cancer in Australia an overview, 2010. The report shows that in 2006, there were 1,226 cases of ovarian cancer diagnosed in Australia, which equates to an average of three women being diagnosed with the disease every day. Between 1982 and 2006, although the overall number of cases increased (largely due to a growing and ageing population) the incidence rate dropped slightly from 12.4 to 10.7 per 100,000 women. The report shows that 40% of women who were diagnosed with ovarian cancer between 2000 and 2006 were alive five years after their diagnosis. This is in contrast to those diagnosed between 1982 and 1987, when only 33% were alive five years after their diagnosis.

Ovarian cancer was the most common cause of gynaecological cancer death and the sixth most common cause of cancer-related death among women in 2006. Almost 800 Australian women, an average of two per day, died from ovarian cancer in 2006. One in 77 women will be diagnosed with ovarian cancer by the time they reach the age of 85. Although the prognosis for women diagnosed with ovarian cancer was relatively poor compared with a number of other cancers, the prognosis has improved over time. These and other data in this report provide a comprehensive picture of ovarian cancer in Australia including how ovarian cancer rates differ by age, Indigenous status, country of birth, socioeconomic status and geographical area.

Report webpage | Report PDF

(More? UNSW Embryology – Ovary Development | Medline Plus – Ovarian Cancer)

Gastrulation: Formation of Embryonic
Mesoderm and Endoderm

The most characteristic event occurring during
the thirdweek of gestation is gastrulation, the process
that establishes all three germ layers (ectoderm,
mesoderm, and endoderm) in the embryo. Gastrulation
begins with formation of the primitive streak on the
surface of the epiblast (Figs. 4.1–4.3A). Initially, the streak
is vaguely defined (Fig. 4.1), but in a 15- to 16-day embryo,
it is clearly visible as a narrow groove with slightly bulging
regions on either side (Fig. 4.2). The cephalic end of the streak,
the primitive node, consists of a slightly elevated area surrounding
the small primitive pit (Fig. 4.3). Cells of the epiblast migrate
toward the primitive streak (Fig. 4.3). Upon arrival in the region
of the streak, they become flask-shaped, detach from the epiblast,
and slip beneath it (Fig. 4.3, B–D). This inward movement is known
as invagination. Once the cells have invaginated, some displace the
hypoblast, creating the embryonic endoderm, and others come to lie
between the epiblast and newly created endoderm to form mesoderm.
Cells remaining in the epiblast then form ectoderm. Thus, the epiblast,
through the process of gastrulation, is the source of all of the germ
layers (Fig. 4.3B), and cells in these layers will give rise to all of the
tissues and organs in the embryo.
As more and more cells move between the epiblast and hypoblast
layers, they begin to spread laterally and cephalad (Fig. 4.3). Gradually,they migrate beyond the margin of the disc and establish contact with the extraembryonic
mesoderm covering the yolk sac and amnion. In the cephalic
direction, they pass on each side of the prechordal plate. The prechordal plate
itself forms between the tip of the notochord and the buccopharyngeal membrane
and is derived from some of the first cells that migrate through the
node in a cephalic direction. Later, the prechordal plate will be important forinduction of the forebrain (Figs. 4.3A and 4.4A). The buccopharyngeal membrane
at the cranial end of the disc consists of a small region of tightly adherent
ectoderm and endoderm cells that represents the future opening of the oral
cavity.
Formation of the Notochord
Prenotochordal cells invaginating in the primitive pit move forward cephalad
until they reach the prechordal plate (Fig. 4.4). These prenotochordal cells
become intercalated in the hypoblast so that, for a short time, the midline of the
embryo consists of two cell layers that form the notochordal plate (Fig. 4.4, B
and C ). As the hypoblast is replaced by endoderm cells moving in at the streak,
cells of the notochordal plate proliferate and detach from the endoderm. They
then form a solid cord of cells, the definitive notochord (Fig. 4.4, D and E ),
which underlies the neural tube and serves as the basis for the axial skeleton.
Because elongation of the notochord is a dynamic process, the cranial end
forms first, and caudal regions are added as the primitive streak assumes a
more caudal position. The notochord and prenotochordal cells extend cranially
to the prechordal plate (an area just caudal to the buccopharyngeal membrane)
and caudally to the primitive pit. At the point where the pit forms an indentationin the epiblast, the neurenteric canal temporarily connects the amniotic and
yolk sac cavities.

Establishment of the Body Axes
Establishment of the body axes, anteroposterior, dorsoventral, and left-right,
takes place before and during the period of gastrulation. The anteroposterior
axis is signaled by cells at the anterior (cranial) margin of the embryonic disc.
This area, the anterior visceral endoderm (AVE), expresses genes essential for
head formation, including the transcription factors OTX2, LIM1, and HESX1
and the secreted factor cerberus. These genes establish the cranial end of the
embryo before gastrulation. The primitive streak itself is initiated and maintained
by expression of Nodal, a member of the transforming growth factor ?
(TGF-?) family (Fig. 4.5). Once the streak is formed, a number of genes regulate
formation of dorsal and ventral mesoderm and head and tail structures.
Another member of the TGF-? family, bone morphogenetic protein-4 (BMP-
4) is secreted throughout the embryonic disc (Fig. 4.5). In the presence of this
protein and fibroblast growth factor (FGF), mesoderm will be ventralized to
contribute to kidneys (intermediate mesoderm), blood, and body wall mesoderm
(lateral plate mesoderm). In fact, all mesoderm would be ventralized if
the activity of BMP-4 were not blocked by other genes expressed in the node.
For this reason, the node is the organizer. It was given that designation byHans Spemann, who first described this activity in the dorsal lip of the blastopore,
a structure analogous to the node, in Xenopus embryos. Thus, chordin
(activated by the transcription factor Goosecoid ), noggin, and follistatin antagonize
the activity of BMP-4. As a result, cranial mesoderm is dorsalized into
notochord, somites, and somitomeres (Fig. 4.5). Later, these three genes are
expressed in the notochord and are important in neural induction in the cranial
region.
As mentioned, Nodal is involved in initiating and maintaining the primitive
streak (Fig. 4.6). Similarly, HNF-3? maintains the node and later induces
regional specificity in the forebrain and midbrain areas. Without HNF-3?, embryos
fail to gastrulate properly and lack forebrain and midbrain structures. As
mentioned previously, Goosecoid activates inhibitors of BMP-4 and contributes
to regulation of head development. Overexpression or underexpression of this
gene results in severe malformations of the head region, including duplications
(Fig. 4.7).
Regulation of dorsal mesoderm formation in mid and caudal regions of the
embryo is controlled by the Brachyury (T) gene (Fig. 4.8). Thus, mesoderm
formation in these regions depends on this gene product, and its absence
results in shortening of the embryonic axis (caudal dysgenesis; see p. 80).
The degree of shortening depends upon the time at which the protein becomes
deficient.
Left-right sidedness, also established early in development, is orchestrated
by a cascade of genes. When the primitive streak appears, fibroblast growth
factor 8 (FGF-8) is secreted by cells in the node and primitive streak andinduces expression of Nodal but only on the left side of the embryo (Fig. 4.9A).
Later, as the neural plate is induced, FGF-8 maintains Nodal expression in the
lateral plate mesoderm (Fig. 4.10), as well as Lefty-2, and both of these genes
upregulate PITX2, a transcription factor responsible for establishing left sidedness
(Fig. 4.9B). Simultaneously, Lefty-1 is expressed on the left side of the
floor plate of the neural tube and may act as a barrier to prevent left-sided signals
from crossing over. Sonic hedgehog (SHH ) may also function in this role
as well as serving as a repressor for left sided gene expression on the right. The
Brachyury(T) gene, another growth factor secreted by the notochord, is also
essential for expression of Nodal, Lefty-1, and Lefty-2 (Fig. 4.9B). Genes regulating
right-sided development are not as well defined, although expression of thetranscription factor NKX 3.2 is restricted to the right lateral plate mesoderm
and probably regulates effector genes responsible for establishing the right side.
Why the cascade is initiated on the left remains a mystery, but the reason may
involve cilia on cells in the node that beat to create a gradient of FGF-8 toward
the left. Indeed, abnormalities in cilia-related proteins result in laterality defects
in mice and some humans with these defects have abnormal ciliary function
.

Teratogenesis Associated With Gastrulation
The beginning of the thirdweek of development, when gastrulation is initiated,
is a highly sensitive stage for teratogenic insult. At this time, fate maps can
be made for various organ systems, such as the eyes and brain anlage, and
these cell populations may be damaged by teratogens. For example, high
doses of alcohol at this stage kill cells in the anterior midline of the germ disc,
producing a deficiency of the midline in craniofacial structures and resulting
in holoprosencephaly. In such a child, the forebrain is small, the two lateral
ventricles often merge into a single ventricle, and the eyes are close together
(hypotelorism). Because this stage is reached 2 weeks after fertilization, it is
approximately 4 weeks from the last menses. Therefore, the woman may not
recognize she is pregnant, having assumed that menstruation is late and will
begin shortly. Consequently, she may not take precautions shewould normally
consider if she knew she was pregnant.
Gastrulation itself may be disrupted by genetic abnormalities and toxic
insults. In caudal dysgenesis (sirenomelia), insufficient mesoderm is formed
in the caudal-most region of the embryo. Because this mesoderm contributes
to formation of the lower limbs, urogenital system (intermediate mesoderm),
and lumbosacral vertebrae, abnormalities in these structures ensue. Affected
individuals exhibit a variable range of defects, including hypoplasia and fusion
of the lower limbs, vertebral abnormalities, renal agenesis, imperforate anus,
and anomalies of the genital organs (Fig. 4.13). In humans, the condition is
associated with maternal diabetes and other causes. In mice, abnormalities
of Brachyury (T), Wnt, and engrailed genes produce a similar phenotype.
Situs inversus is a condition in which transposition of the viscera in the
thorax and abdomen occurs. Despite this organ reversal, other structural abnormalities
occur only slightly more frequently in these individuals. Approximately
20% of patients with complete situs inversus also have bronchiectasis
and chronic sinusitis because of abnormal cilia (Kartagener syndrome). Interestingly,
cilia are normally present on the ventral surface of the primitive node
and may be involved in left-right patterning during gastrulation. Other conditions
of abnormal sidedness are known as laterality sequences. Patients with
these conditions do not have complete situs inversus but appear to be predominantly
bilaterally left sided or right sided. The spleen reflects the differences;
those with left-sided bilaterality have polysplenia, and those with right-sided
bilaterality have asplenia or hypoplastic spleen. Patients with laterality sequences
also are likely to have other malformations, especially heart defects.

The most characteristic event occurring during the third week is gastrulation,
which begins with the appearance of the primitive streak,
which has at its cephalic end the primitive node. In the region of the
node and streak, epiblast cells move inward (invaginate) to form new cell layers,
endoderm and mesoderm. Hence, epiblast gives rise to all three germ
layers in the embryo. Cells of the intraembryonic mesodermal germ layer
migrate between the two other germ layers until they establish contact with
the extraembryonic mesoderm covering the yolk sac and amnion (Figs. 4.3
and 4.4).
Prenotochordal cells invaginating in the primitive pit move forward until
they reach the prechordal plate. They intercalate in the endoderm as the notochordal
plate (Fig. 4.4). With further development, the plate detaches from the
endoderm, and a solid cord, the notochord, is formed. It forms a midline axis,
84 Part One: General Embryology
Figure 4.18 Stem villi (SV) extend from the chorionic plate (CP) to the basal plate (BP).
Terminal villi (arrows) are represented by fine branches from stem villi.
which will serve as the basis of the axial skeleton (Fig. 4.4). Cephalic and caudal
ends of the embryo are established before the primitive streak is formed.
Thus, cells in the hypoblast (endoderm) at the cephalic margin of the disc form
the anterior visceral endoderm that expresses head-forming genes, including
OTX2, LIM1, and HESX1 and the secreted factor cerberus. Nodal, a member
of the TGF-? family of genes, is then activated and initiates and maintains the
integrity of the node and streak. BMP-4, in the presence of FGF, ventralizes
mesoderm during gastrulation so that it forms intermediate and lateral plate
mesoderm. Chordin, noggin, and follistatin antagonize BMP-4 activity and
dorsalize mesoderm to form the notochord and somitomeres in the head region.
Formation of these structures in more caudal regions is regulated by the
Brachyury (T) gene. Left-right asymmetry is regulated by a cascade of genes;
first, FGF-8, secreted by cells in the node and streak, induces Nodal and Lefty-2
expression on the left side. These genes upregulate PITX2, a transcription factor
responsible for left sidedness.
Epiblast cells moving through the node and streak are predetermined by
their position to become specific types of mesoderm and endoderm. Thus, it is
possible to construct a fate map of the epiblast showing this pattern (Fig. 4.11).
Chapter 4: Third Week of Development: Trilaminar Germ Disc 85
By the end of the third week, three basic germ layers, consisting of ectoderm,
mesoderm, and endoderm, are established in the head region, and
the process continues to produce these germ layers for more caudal areas of
the embryo until the end of the 4th week. Tissue and organ differentiation has
begun, and it occurs in a cephalocaudal direction as gastrulation continues.
In the meantime, the trophoblast progresses rapidly. Primary villi obtain
a mesenchymal core in which small capillaries arise (Fig. 4.17). When these
villous capillaries make contact with capillaries in the chorionic plate and connecting
stalk, the villous syste

Infertility is a problem for 15% to 30% of couples. Male infertility may be
a result of insufficient numbers of sperm and/or poor motility. Normally, the
ejaculate has a volume of 3 to 4 ml, with approximately 100 million sperm
per ml. Males with 20 million sperm per ml or 50 million sperm per total
ejaculate are usually fertile. Infertility in a woman may be due to a number of
causes, including occluded oviducts (most commonly caused by pelvic inflammatory
disease), hostile cervical mucus, immunity to spermatozoa, absence
of ovulation, and others.
In vitro fertilization (IVF) of human ova and embryo transfer is a frequent
practice conducted by laboratories throughout the world. Follicle growth in the
ovary is stimulated by administration of gonadotropins. Oocytes are recovered
by laparoscopy from ovarian follicles with an aspirator just before ovulation
when the oocyte is in the late stages of the first meiotic division. The egg is
placed in a simple culture medium and sperm are added immediately. Fertilized
eggs are monitored to the eight-cell stage and then placed in the uterus
to develop to term. Fortunately, because preimplantation-stage embryos are
resistant to teratogenic insult, the risk of producing malformed offspring by
in vitro procedures is low.
A disadvantage of IVF is its low success rate; only 20% of fertilized ova
implant and develop to term. Therefore, to increase chances of a successful
pregnancy, four or five ova are collected, fertilized, and placed in the uterus.
This approach sometimes leads to multiple births.
Another technique, gamete intrafallopian transfer (GIFT), introduces
oocytes and sperm into the ampulla of the fallopian (uterine) tube, where
42 Part One: General Embryology
fertilization takes place. Development then proceeds in a normal fashion. In a
similar approach, zygote intrafallopian transfer (ZIFT), fertilized oocytes are
placed in the ampullary region. Both of these methods require patent uterine
tubes.
Severe male infertility, in which the ejaculate contains very few live sperm
(oligozoospermia) or even no live sperm (azoospermia), can be overcome
using intracytoplasmic sperm injection (ICSI). With this technique, a single
sperm, which may be obtained from any point in the male reproductive tract,
is injected into the cytoplasm of the egg to cause fertilization. This approach
offers couples an alternative to using donor sperm for IVF. The technique
carries an increased risk for fetuses to have Y chromosome deletions but no
other chromosomal abnormalities.

Day 8
At the eighth day of development, the blastocyst is partially
embedded in the endometrial stroma. In the area over the embryoblast,
the trophoblast has differentiated into two layers:
(a) an inner layer of mononucleated cells, the cytotrophoblast,
and (b) an outer multinucleated zone without distinct cell boundaries,
the syncytiotrophoblast (Figs. 3.1 and 3.2). Mitotic figures are
found in the cytotrophoblast but not in the syncytiotrophoblast. Thus,
cells in the cytotrophoblast divide and migrate into the syncytiotrophoblast,
where they fuse and lose their individual cell membranes.
Cells of the inner cell mass or embryoblast also differentiate into two
layers: (a) a layer of small cuboidal cells adjacent to the blastocyst cavity,
known as the hypoblast layer, and (b) a layer of high columnar cells
adjacent to the amniotic cavity, the epiblast layer (Figs. 3.1 and 3.2).
Together, the layers form a flat disc. At the same time, a small cavity
appears within the epiblast. This cavity enlarges to become theamniotic cavity. Epiblast cells adjacent to the cytotrophoblast are called amnioblasts;
together with the rest of the epiblast, they line the amniotic cavity
(Figs. 3.1 and 3.3). The endometrial stroma adjacent to the implantation site
is edematous and highly vascular. The large, tortuous glands secrete abundant
glycogen and mucus.

Day 9
The blastocyst is more deeply embedded in the endometrium, and the penetration
defect in the surface epithelium is closed by a fibrin coagulum (Fig. 3.3).
The trophoblast shows considerable progress in development, particularly at
the embryonic pole, where vacuoles appear in the syncytium. When these vacuoles
fuse, they form large lacunae, and this phase of trophoblast development
is thus known as the lacunar stage (Fig. 3.3).
At the abembryonic pole, meanwhile, flattened cells probably originating
from the hypoblast form a thin membrane, the exocoelomic (Heuser’s) membrane,
that lines the inner surface of the cytotrophoblast (Fig. 3.3). This membrane,
together with the hypoblast, forms the lining of the exocoelomic cavity,
or primitive yolk sac.

Days 11 and 12
By the 11th to 12th day of development, the blastocyst is completely embedded
in the endometrial stroma, and the surface epithelium almost entirely covers
the original defect in the uterine wall (Figs. 3.4 and 3.5). The blastocyst now
produces a slight protrusion into the lumen of the uterus. The trophoblast is
characterized by lacunar spaces in the syncytium that form an intercommunicating
network. This network is particularly evident at the embryonic pole; at
the abembryonic pole, the trophoblast still consists mainly of cytotrophoblastic
cells (Figs. 3.4 and 3.5).
Concurrently, cells of the syncytiotrophoblast penetrate deeper into the
stroma and erode the endothelial lining of the maternal capillaries. These capillaries,
which are congested and dilated, are known as sinusoids. The syncytial
lacunae become continuous with the sinusoids and maternal blood enters the
lacunar system (Fig. 3.4). As the trophoblast continues to erode more and more
sinusoids, maternal blood begins to flow through the trophoblastic system, establishing
the uteroplacental circulation.
In the meantime, a new population of cells appears between the inner
surface of the cytotrophoblast and the outer surface of the exocoelomiccavity. These cells, derived from yolk sac cells, form a fine, loose connective
tissue, the extraembryonic mesoderm, which eventually fills all of the
space between the trophoblast externally and the amnion and exocoelomic
membrane internally (Figs. 3.4 and 3.5). Soon, large cavities develop in the
extraembryonic mesoderm, and when these become confluent, they form
a new space known as the extraembryonic coelom, or chorionic cavity
(Fig. 3.4). This space surrounds the primitive yolk sac and amniotic cavity except
where the germ disc is connected to the trophoblast by the connecting stalk
(Fig. 3.6). The extraembryonic mesoderm lining the cytotrophoblast and amnion
is called the extraembryonic somatopleuric mesoderm; the lining covering
the yolk sac is known as the extraembryonic splanchnopleuric mesoderm
(Fig. 3.4).
Growth of the bilaminar disc is relatively slowcompared with that of the trophoblast;
consequently, the disc remains very small (0.1–0.2 mm). Cells of the
endometrium, meanwhile, become polyhedral and loaded with glycogen and
lipids; intercellular spaces are filled with extravasate, and the tissue is edematous.
These changes, known as the decidua reaction, at first are confined to the
area immediately surrounding the implantation site but soon occur throughout
the endometrium.

Day 13
By the 13th day of development, the surface defect in the endometrium has
usually healed. Occasionally, however, bleeding occurs at the implantation site
as a result of increased blood flow into the lacunar spaces. Because this bleeding
occurs near the 28th day of the menstrual cycle, it may be confused withnormal menstrual bleeding and, therefore, cause inaccuracy in determining
the expected delivery date.
The trophoblast is characterized by villous structures. Cells of the cytotrophoblast
proliferate locally and penetrate into the syncytiotrophoblast,
forming cellular columns surrounded by syncytium. Cellular columns with
the syncytial covering are known as primary villi (Figs. 3.6 and 3.7) (see
Chapter 4).
In the meantime, the hypoblast produces additional cells that migrate along
the inside of the exocoelomic membrane (Fig. 3.4). These cells proliferate and
gradually form a new cavity within the exocoelomic cavity. This new cavity is
known as the secondary yolk sac or definitive yolk sac (Figs. 3.6 and 3.7). This
yolk sac is much smaller than the original exocoelomic cavity, or primitive yolk
sac. During its formation, large portions of the exocoelomic cavity are pinched
off. These portions are represented by exocoelomic cysts, which are often
found in the extraembryonic coelom or chorionic cavity (Figs. 3.6 and 3.7).
Meanwhile, the extraembryonic coelom expands and forms a large cavity,
the chorionic cavity. The extraembryonic mesoderm lining the inside of the
cytotrophoblast is then known as the chorionic plate. The only place where
extraembryonic mesoderm traverses the chorionic cavity is in the connecting
stalk (Fig. 3.6). With development of blood vessels, the stalk becomes the
umbilical cord.

At the beginning of the second week, the blastocyst is partially embedded
in the endometrial stroma. The trophoblast differentiates into (a)
an inner, actively proliferating layer, the cytotrophoblast, and (b) an
outer layer, the syncytiotrophoblast, which erodes maternal tissues (Fig. 3.1).
By day 9, lacunae develop in the syncytiotrophoblast. Subsequently, maternal
sinusoids are eroded by the syncytiotrophoblast, maternal blood enters the
lacunar network, and by the end of the second week, a primitive uteroplacental
circulation begins (Fig. 3.6). The cytotrophoblast, meanwhile, forms
cellular columns penetrating into and surrounded by the syncytium. These
columns are primary villi. By the end of the second week, the blastocyst
is completely embedded, and the surface defect in the mucosa has healed
(Fig. 3.6).
The inner cell mass or embryoblast, meanwhile, differentiates into (a) the
epiblast and (b) the hypoblast, together forming a bilaminar disc (Fig. 3.1).
Epiblast cells give rise to amnioblasts that line the amniotic cavity superior
to the epiblast layer. Endoderm cells are continuous with the exocoelomic
membrane, and together they surround the primitive yolk sac (Fig. 3.4). By
the end of the second week, extraembryonic mesoderm fills the space between
the trophoblast and the amnion and exocoelomic membrane internally. When
vacuoles develop in this tissue, the extraembryonic coelom or chorionic cavity
forms (Fig. 3.6). Extraembryonic mesoderm lining the cytotrophoblast and
62 Part One: General Embryology
amnion is extraembryonic somatopleuric mesoderm; the lining surrounding
the yolk sac is extraembryonic splanchnopleuric mesoderm (Fig. 3.6).
The second week of development is known as the week of twos: The
trophoblast differentiates into two layers, the cytotrophoblast and syncytiotrophoblast.
The embryoblast forms two layers, the epiblast and hypoblast.
The extraembryonic mesoderm splits into two layers, the somatopleure and
splanchnopleure. And two cavities, the amniotic and yolk sac cavities, form.
Implantation occurs at the end of the first week. Trophoblast cells invade the
epithelium and underlying endometrial stroma with the help of proteolytic enzymes.
Implantationmay also occur outside the uterus, such as in the rectouterine
pouch, on the mesentery, in the uterine tube, or in the ovary (ectopic pregnancies).

SPERMATOGENESIS
Maturation of Sperm Begins at Puberty
Spermatogenesis, which begins at puberty, includes all of the events by which
spermatogonia are transformed into spermatozoa. At birth, germ cells in the
male can be recognized in the sex cords of the testis as large, pale cells surrounded
by supporting cells (Fig. 1.21A). Supporting cells, which are derived
from the surface epithelium of the gland in the same manner as follicular cells,
become sustentacular cells, or Sertoli cells (Fig. 1.21C ).
Shortly before puberty, the sex cords acquire a lumen and become the
seminiferous tubules. At about the same time, primordial germ cells give
rise to spermatogonial stem cells. At regular intervals, cells emerge from this
stem cell population to form type A spermatogonia, and their production
marks the initiation of spermatogenesis. Type A cells undergo a limited number
of mitotic divisions to form a clone of cells. The last cell division produces
type B spermatogonia, which then divide to form primary spermatocytes
(Figs. 1.21 and 1.22). Primary spermatocytes then enter a prolongedprophase (22 days) followed by rapid completion of meiosis I and formation
of secondary spermatocytes. During the second meiotic division, these cells
immediately begin to form haploid spermatids (Figs. 1.21–1.23). Throughout
this series of events, from the time type A cells leave the stem cell population
to formation of spermatids, cytokinesis is incomplete, so that successive
cell generations are joined by cytoplasmic bridges. Thus, the progeny of a single
type A spermatogonium form a clone of germ cells that maintain contact
throughout differentiation (Fig. 1.22). Furthermore, spermatogonia and spermatids
remain embedded in deep recesses of Sertoli cells throughout their
development (Fig. 1.24). In this manner, Sertoli cells support and protect the
germ cells, participate in their nutrition, and assist in the release of mature
spermatozoa.
Spermatogenesis is regulated by luteinizing hormone (LH) production by
the pituitary. LH binds to receptors on Leydig cells and stimulates testosterone
production, which in turn binds to Sertoli cells to promote spermatogenesis.
Follicle stimulating hormone (FSH) is also essential because its binding to
Sertoli cells stimulates testicular fluid production and synthesis of intracellular
androgen receptor proteins.
Spermiogenesis
The series of changes resulting in the transformation of spermatids into spermatozoa
is spermiogenesis. These changes include (a) formation of the acrosome,
which covers half of the nuclear surface and contains enzymes to assist in penetration
of the egg and its surrounding layers during fertilization (Fig. 1.25);
(b) condensation of the nucleus; (c) formation of neck, middle piece, and tail;
and (d) shedding of most of the cytoplasm. In humans, the time required for
a spermatogonium to develop into a mature spermatozoon is approximately
64 days.
When fully formed, spermatozoa enter the lumen of seminiferous tubules.
From there, they are pushed toward the epididymis by contractile elements
in the wall of the seminiferous tubules. Although initially only slightly motile,
spermatozoa obtain full motility in the epididymis.

Abnormal Gametes
In humans and in most mammals, one ovarian follicle occasionally contains
two or three clearly distinguishable primary oocytes (Fig. 1.26A). Although
these oocytes may give rise to twins or triplets, they usually degenerate before
reaching maturity. In rare cases, one primary oocyte contains two or even
three nuclei (Fig. 1.26B). Such binucleated or trinucleated oocytes die before
reaching maturity.
In contrast to atypical oocytes, abnormal spermatozoa are seen frequently,
and up to 10% of all spermatozoa have observable defects. The
head or the tail may be abnormal; spermatozoa may be giants or dwarfs;
and sometimes they are joined (Fig. 1.26C ). Sperm with morphologic abnormalities
lack normal motility and probably do not fertilize oocytes.

Primordial germ cells appear in the wall of the yolk sac in the fourth
week and migrate to the indifferent gonad (Fig. 1.1), where they arrive
at the end of the fifth week. In preparation for fertilization, both
male and female germ cells undergo gametogenesis, which includes meiosis
and cytodifferentiation. During meiosis I, homologous chromosomes
pair and exchange genetic material; during meiosis II, cells fail to replicate
DNA, and each cell is thus provided with a haploid number of chromosomes
and half the amount of DNA of a normal somatic cell (Fig. 1.3). Hence, mature
male and female gametes have, respectively, 22 plus X or 22 plus Y
chromosomes.
Birth defects may arise through abnormalities in chromosome number
or structure and from single gene mutations. Approximately 7% of major
Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 29
birth defects are a result of chromosome abnormalities, and 8%, are a result
of gene mutations. Trisomies (an extra chromosome) and monosomies
(loss of a chromosome) arise during mitosis or meiosis. During meiosis, homologous
chromosomes normally pair and then separate. However, if separation
fails (nondisjunction), one cell receives too many chromosomes and
one receives too few (Fig. 1.5). The incidence of abnormalities of chromosome
number increases with age of the mother, particularly with mothers
aged 35 years and older. Structural abnormalities of chromosomes include
large deletions (cri-du-chat syndrome) and microdeletions. Microdeletions
involve contiguous genes that may result in defects such as Angelman syndrome
(maternal deletion, chromosome 15q11–15q13) or Prader-Willi syndrome
(paternal deletion, 15q11–15q13). Because these syndromes depend
on whether the affected genetic material is inherited from the mother or the
father, they also are an example of imprinting. Gene mutations may be dominant
(only one gene of an allelic pair has to be affected to produce an alteration)
or recessive (both allelic gene pairs must be mutated). Mutations responsible
for many birth defects affect genes involved in normal embryological
development.
In the female, maturation fromprimitive germ cell to mature gamete, which
is called oogenesis, begins before birth; in the male, it is called spermatogenesis,
and it begins at puberty. In the female, primordial germ cells form
oogonia. After repeated mitotic divisions, some of these arrest in prophase of
meiosis I to form primary oocytes. By the seventh month, nearly all oogonia
have become atretic, and only primary oocytes remain surrounded by
a layer of follicular cells derived from the surface epithelium of the ovary
(Fig. 1.17). Together, they form the primordial follicle. At puberty, a pool of
growing follicles is recruited and maintained from the finite supply of primordial
follicles. Thus, everyday 15 to 20 follicles begin to grow, and as they mature,
they pass through three stages: 1) primary or preantral; 2) secondary
or antral (vesicular, Graafian); and 3) preovulatory. The primary oocyte remains
in prophase of the first meiotic division until the secondary follicle is
mature. At this point, a surge in luteinizing hormone (LH) stimulates preovulatory
growth: meiosis I is completed and a secondary oocyte and polar
body are formed. Then, the secondary oocyte is arrested in metaphase of
meiosis II approximately 3 hours before ovulation and will not complete this
cell division until fertilization. In the male, primordial cells remain dormant
until puberty, and only then do they differentiate into spermatogonia. These
stem cells give rise to primary spermatocytes, which through two successive
meiotic divisions produce four spermatids (Fig. 1.4). Spermatids go through
a series of changes (spermiogenesis) (Fig. 1.25) including (a) formation of
the acrosome, (b) condensation of the nucleus, (c) formation of neck, middle
piece, and tail, and (d) shedding of most of the cytoplasm. The time required
for a spermatogonium to become a mature spermatozoon is approximately
64 days.