Germ Cell and Fertilization 1

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Germ cells, fertilization,

and sex

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Phases of Embryonic Development

1. gametogenesis
2. fertilization
3. cleavage
4. blastulation
5. gastrulation
6. neurulation
7. organogenesis

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Reproduction and sex

•A great deal of the biology of animals and plants


•The embryos of all sexually reproducing organisms develop
from a single cell, formed by the fusion of a male and a female
gamete at fertilization
•The embryos of all sexually reproducing organisms develop
from a single cell, formed by the fusion of a male and a female
gamete at fertilization
•The importance of sexual reproduction is that it keeps
generating new genotypes by bringing together the genes from
two different individuals, male and female, in the fertilized egg
•A key issue in sexual development is how the germ cells are
specified.

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Great variety in reproduction

•Animals reproduce sexually

•Some animals can reproduce asexually, such as Hydra, which can


reproduce by budding

•Turtles, whose eggs can develop without being fertilized.

•Plants, although reproducing sexually, differ from most animals in that


their germ cells are not specified early in embryonic development, but
during the development of the flowers from the floral meristems.

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• There is a fundamental distinction between the germline cell (germ
cells) and the somatic or body cells.
• The gametes: eggs and sperms
Gametogenesis is a process by which the diploid germ cellsis a process
by which the diploid germ cells undergo a number of chromosomal
and morphological changes to form mature haploid gametes.
• Animals produce gametes directly through meiosis in organs called
gonads.
• Precursor germ cells are known as primordial germ cell.
• MalesMales and femalesMales and females of a species that
reproduces sexually have different forms of gametogenesis:
• Spermatogenesis (male) in testes produce sperms.
• Oogenesis (female) in Ovary produce ova.
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Somatic Cells:

• Found in all body tissues except gonads.


• Contain diploid numbers of chromosomes (2N).
• Replacement of dead cells
• Reproduce by mitotic division.
• Functions:
1. Responsible for formation of different system and
organs.
2. Have other specific functions
eg.: muscular system have myoplast for contraction and
relaxation .
nervous system have neurons for transmission of
impulses.
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Germ Cells:

• Found only in gonads (testes & ovary)


• Contain haploid number of chromosomes
(1N)
• Reproduce by meiotic division (meiosis).
• Function : Formation of gametes (male &
female)

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Primordial germ cells

In animals, once the primordial germ cells are specified,


they migrate into the gonads, somatic structures that
usually develop some distance away from the site of
germ cell origin.

Once within the gonads, the germ cells differentiate as


either male or female gametes.

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Germ-cell fate can be specified by a distinct
germ plasm in the egg

In flies, nematodes, and frogs, molecules


localized in specialized cytoplasm in the egg
are involved in specifying the germ cells.

The clearest example of this is in Drosophila,


where primordial germ cells known as pole
cells become distinct at the posterior pole of
the egg about 90 minutes after fertilization,
more than an hour before cellularization of
the rest of the embryo.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Germ-cell fate can be specified by a distinct
germ plasm in the egg

In flies, nematodes, and frogs, molecules localized in specialized cytoplasm in


the egg are involved in specifying the germ cells.

The clearest example of this is in Drosophila, where primordial germ cells known
as pole cells become distinct at the posterior pole of the egg about 90 minutes
after fertilization, more than an hour before cellularization of the rest of the
embryo.

The cytoplasm at the posterior pole is called pole plasm and is distinguished by
large organelles, the polar granules, which contain both proteins and RNAs.

What is special about the cytoplasm at the posterior pole?

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


What is special about the cytoplasm at the
posterior pole?
Two experiments demonstrate it something special

First, if the posterior end of the egg is irradiated with


ultraviolet light, which destroys the pole plasm activity,
no germ cells develop, although somatic cells in that
regions do develop.
Second, if pole plasm of an egg is transferred to the
anterior pole of another embryo, the nuclei that become
surrounded by the pole plasm are specified as germ
cells nuclei.

If the anterior cells containing pole plasm are


transplanted into the posterior pole region of a third
embryo, they develop as functional germ cells.

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Specific gene in the germ plasm of Drosophila

• In normal eggs, Oskar mRNA is localized at the


posterior end of the embryo, where as bicoid mRNA is
at the anterior end.

• The localization signal in both bicoid and oskar mRNA


are in their 3’ untranslated region.

• By manipulating the Drosophila DNA, the localization


signal of oskar can be replaced by that of bicoid.

• A transgenic fly is made containing the modified DNA

• The egg has oskar mRNA at both end

• Oskar alone is sufficient to initiate the specification of


germ cells.
Some protein become asymmetrically distributed to
germline

P granules and PIE-1, protein become


asymmetrically distributed to germline cells
during cleavage of the nematode egg.
Before fertilization, P granules are
distributed throughout the egg.
After fertilization P granules become
localized at the posterior end of the egg.
At the first cleavage, they are only included
in the P1 cell (top panel), and thus become
confined to the P cell lineage.
The PIE1 protein is only present in P cells.
All germ cells are derived from P4, which
is formed at the fourth cleavage

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In mammals germ cells are induced by cell-cell
interaction

• There is no evidence for germ plasm in the mouse or other mammals or in chick.
• It is less prevalent mode of germline specification in animal generally
• Germ-cell specification in the mouse involve cell-cell interaction
• The earliest detectable primordial germ cells can be identified in the mouse proximal
epiblast just before the beginning of gastrulation. They form a cluster of six to eight cells
expressing the transcriptional repressor protein Blimp1.

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In mammals germ cells are induced by cell-cell
interaction

First panel: A small number of primordial germ cells (PGCs)(white) expressing Blimp1
Second panel: During gastrulation, these cells and their surrounding prospective extra
embryonic mesoderm move to the posterior end of the embryo above the
primitive streak, where the PGCs start also to express the germ cell lineage
gene stella, around 40 PGCs (orange) are present in the primitive streak
Panel third: PGCS starts to migrate to the gonads.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Germ cells migrate from their site of origin to
the gonad

• In many animals, germ cells develop at some distance from the gonads
and only later migrate to them, where they differentiate into eggs or sperm.
• The reason for this separation of site of origin from final destination is not
known.

But it may be

• A mechanism for excluding germ cells from the general developmental


upheaval involved in laying down the body plan.
or
• A mechanism for selecting the healthiest of the germ cells, namely
those that survive migration.

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Germ cells migrate from their site of origin to
the gonad
Examples

• The vertebrate gonad develops from the mesoderm


lining the abdominal cavity, which is known as the
genital ridge.
• The number of primordial germ cells that arrive
at the genital ridge of the mouse is about 8000,
starting from the a population of around 40 at
the posterior end of the primitive streak.
• In Xenopus, the primordial germ cells originating in the
floor of the blastocoel migrate to the future gonad along
a cell sheet that joins the gut to the genital ridge.
• Only a small number of cells start this journey,
dividing about three times before arrival, so that
about 30 germ cells colonize the gonad.
• In chick embryos, the pattern of migration is different: the germ cells originate at the
head end of the embryo, and most arrive at their destination via the blood vessels,
leaving the bloodstream at the hindgut and then migrating along the epithelial sheet.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Germ cells are guided to their final destination
by chemical signal

• All migrating gem cells are continuously receiving signals for guidance, survival, and
proliferation from the tissues through which they migrate.
• The main guidance cue in both zebra fish and mice seems to be chemoattractant
protein SDF-1
• The mouse SDF-1 alpha, seems to act as a guidance cue for migration
• sdf-1 mRNA is expressed in locations where PGCs are found and towards which they
migrate at the time they leave the blood vessels. 
• In Drosophila , the gene wunen is involved in repelling germ cells from the rest of the
gut, and so preventing them from dispersing before they reach the gonadal
mesoderm, whereas expression of the enzyme HMGCoA reductase in the
prospective gonad is needed for the germ cells to be attracted toward the prospective
gonad.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Germ-cell differentiation involves halving of
chromosome number by meiosis

• Meiosis reduces the number of chromosomes from the diploid to


the haploid number.
• Only one pair of homologous chromosomes is shown here for
simplicity. Before the first meiotic division the DNA replicates, so
that each chromosome entering meiosis is composed of two
identical chromatids.
• The paired homologous chromosomes (known as a bivalent)
undergo crossing over and recombination. and align on the meiotic
spindle at the metaphase of the first meiotic division.
• The homologolls chromosomes separate, and each is segregated
into a different daughter cell at the first cell division.
• There is no DNA replication before the second meiotic division.
• The daughter chromatids of each chromosome separate and
segregate at the second cell division.
• The chromosome number of the resulting daughter celts is thus
halved.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Oogenesis and spermatogenesis in
mammals

After the germ cells that form oocytes enter the embryonic
ovary, they divide mitotically a few times and then enter the
prophase of the first meiotic division.
No further cell multiplication occurs.
Further development occurs in the sexually mature adult
female. This includes a 100-fold increase in mass, the
formation of external cell coats, and the development of a
layer of cortical granules located under the oocyte plasma
membrane in each cycle.
A group of follicles starts to grow, oocyte growth and
maturation follows: a few eggs are ovulated but most
degenerate.
Eggs continue to mature in the ovary under hormonal
influences, but become blocked in the second metaphase
of meiosis, which is only completed after fertilization.

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Polar bodies are formed at meiosis

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Oogenesis and spermatogenesis
in mammals

Germ cells that develop into sperm enter the


embryonic: testes and become arrested at the
G1 stage of the cell cycle.
After birth, they begin to divide mitotically again,
forming a population of stem cells
(spermatogonia).
These give off cells that then undergo meiosis
and differentiate into sperm. Sperm can
therefore be produced indefinitely.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Oogenesis and spermatogenesis
in mammals

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Paternal and maternal genomes are both required
for normal mouse development

• A normal biparental embryo has contributions from both the paternal and
maternal nuclei in the zygote after fertilization (left panel).
• Using nuclear transplantation, an egg can be constructed with two paternal or
two maternal nuclei from an inbred strain.
• Embryos that develop from an egg with two maternal genomes gynogenetic
embryos (center panel) have underdeveloped extra-embryonic structures.
• This results in development being
blocked, although the embryo itself is
relatively normal and well developed.
• Embryos that develop from eggs with
two paternal genomes androgenetic
embryos (right panel) have normal
extra-embryonic structures, but the
embryo itself only develops to a stage
where a few somites have formed.

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Imprinting of genes controlling embryonic
growth
• In mouse embryos the paternal gene for Insulin-like growth factor 2 (Igf-2) is
on, but the gene on the maternal chromosome is off.
• In contrast the ' Igf-2’ gene is on in the maternal genome and off in the
paternal genome.
• The product of this gene tends to inhibit growth, as it is involved in degrading
IGF·2. H19 may regulate Igf-2.

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Summary of germ cell

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


A human sperm

• The acrosomal vesicle at the anterior end of the sperm contains


enzymes that are used to digest the protective coats around the egg.
• The plasma membrane on the head of the sperm contains various
specialized proteins that bind to the egg coats and facilitate entry.
• The sperm moves by its single flagellum, which is powered by
mitochondria.
• The overall length from head to tail is about 60μm.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Getting to the right site:

• Helping the sperm:


– At ovulation, the cervical mucus increases in amount and becomes less
thick, allowing easier sperm transport.
– Passage of the sperm through the uterus and oviduct occurs mainly due to
muscular contractions of these organs.
• Oocyte:
– The ends of the oviducts come into close contact with the ovary during
ovulation.
– Fimbriae of oviduct ends “sweep” the ovulated ovum into the oviduct.
– Peristaltic waves of oviduct musculature bring the ovum into the ampulla of
the oviduct.
The Oviduct
H & E (Hematoxylin and eosin stain) × 10

M = muscle
BL = broad ligament
S = serosa with vascular
supporting tissue

From Wheater’s Functional Histology, 4th ed., 2000.


Morphology of the Oviduct:

Fallopian tube S = smooth muscle


H & E × 150 E = ciliated epithelium Fallopian tube
From Wheater’s Functional Histology, 4th ed., 2000. Azan × 320
Capacitation: readying the sperm

• Sperms cannot fertilize oocytes when they are newly


ejaculated.
• The process of capacitation takes 5-7 hours.
• Capacitated sperms are more active.
• Location: capacitation occurs in the uterus and oviducts and
is facilitated by substances of the female genital tract.
• The acrosomal reaction cannot occur until capacitation has
occurred.
Stage 1 of fertilization:

• The acrosome reaction must be completed before the sperm can


fuse with the secondary oocyte
– Occurs when sperms come into contact with the corona
radiata of the oocyte
– Perforations develop in the acrosome
– Point fusions of the sperm plasma membrane and the
external acrosomal membrane occur
– The acrosome reaction is associated with the release of
acrosome enzymes that facilitate fertilization
• Passage of sperm through the corona radiata depends on
enzyme action:
– hyaluronidase released from sperm acrosome
– Tubal mucosal enzymes
• Flagella action also aids corona radiata penetration
Fertilization of a mammalian egg

• After penetrating the follicle-derived


cumulus cell layer the sperm binds to the
zona pellucida(1).
• This triggers the acrosomal reaction (2).
in which enzymes are released from the
acrosomal vesicle and break down the
zona pellucida.
• This enables the sperm to penetrate the
zona pellucid a (3) and bind to the egg
plasma membrane.
• The plasma membrane of the sperm
head fuses with the egg plasma
membrane (4).
• This activates the egg causing a release
of cortical granules and the sperm
nucleus then enters the egg (5).
(After Alberts, B . . et 01.: 1989.)
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Ovum and sperms: (In vitro)

From this photograph, it should be


clear that the heads of human
sperm are less than 1/20 the
diameter of human eggs.

→ Arrows point to sperm heads

Advanced Fertility Center of Chicago


http://www.advancedfertility.com/

The surfaces of unfertilized eggs are usually smooth in appearance. The mottled look
of this egg is not normally seen, but apparently all the ova from this woman had this
appearance.
Stage 2 of fertilization:

• Penetration of the zona pellucida around the oocyte:


– Acrosomal enzymes: esterases, acrosin, and
neuraminidase cause lysis of the zona pellucida
• Once sperm penetrates zona pellucida, the zona reaction
occurs:
– This reaction makes the zona pellucida impermeable to
other sperms.
– When more than one sperm manages to enter the ovum
(dispermy = 2; triploidy = 3), the fetus nearly always
aborts.
Changes in the egg membrane at
fertilization block polyspermy
Depolarization of egg plasma membrane
Depolarization of the sea urchin egg plasma membrane at fertilization.
The resting membrane potential of the unfertilized sea urchin egg is -70 mV at
fertilization.
It changes rapidly to + 20 mV, and then slowly returns to the original value.
This depolarization may provide a fast block to polyspermy.

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Changes in the egg membrane at
fertilization block polyspermy

The cortical reaction at fertilization in the sea urchin.


•The egg is surrounded by a vitelline membrane, which lies outside the plasma membrane.
•Membrane bound cortical granules lie just beneath the egg plasma membrane.
•At fertilization the cortical granules fuse with the plasma membrane and some of the
contents are extruded by exocytosis.
•These join with the vitelline membrane to form a tough fertilization membrane, which then
lifts off the egg surface and prevents further sperm entry.
•Other cortical granule constituents give rise to a hyaline layer, which surrounds the egg
under the fertilization membrane.

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A calcium wave initiated at fertilization results
in egg activation

• A series of images showing an intracellular calcium wave at Fertilization in a


sea urchin egg.
• The fertilizing sperm has fused just to the left of the top of the egg, and
triggered the wave.
• Calcium ion concentration is monitored with a calcium sensitive fluorescent
dye, using confocal fluorescence microscopy.
• Calcium concentration is shown in false color: red is the highest
concentration, then yellow, green, and blue.
• Times shown are seconds after sperm entry.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Stages 3 & 4 of fertilization:

• Fusion of plasma membranes of oocyte and


sperm
– Head and tail of a sperm enter the cytoplasm of
the oocyte, but the sperm plasma membrane
remains behind.
• 2nd meiotic division of oocyte is completed
– The secondary oocyte was previously arrested
in metaphase of the 2nd meiotic division, and
now forms the mature ovum and another polar
body.
Stage 5 of fertilization:
• Formation of male and female pronuclei:
– Chromosomal material of the sperm decondensates
and enlarges
– Chromosomal material of the ovum decondensates
following the completion of meiosis
• At this stage, the male and female pronuclei are
indistinguishable.
• As they grow, the pronuclei replicate their DNA → still 1N
(haploid)- 23 chromosomes, each in chromatid pairs
Fusion of the pronuclei:
(in vitro)

• The male and female


pronuclei are
indistinguishable from one
another.
• The second polar body can
be seen (arrow).
• The plasma membranes of
the two pronuclei are
dissolving and one diploid
nucleus will remain.

Advanced Fertility Center of Chicago


http://www.advancedfertility.com/
Stage 6 of fertilization:

• Membranes of the pronuclei break down,


chromosomes condense and arrange
themselves for mitotic cell division
– On membrane dissolution, there is 1 cell with
46 chromosomes = diploid (2N)
– The first cleavage follows shortly, leaving 2
cells, each with 46 chromosomes.
• Mitosis in the new zygote uses centrioles derived
from the sperm. The oocyte has no centrioles.
Fertilization facts:
• Completed within 24 hours of ovulation
• Approximately 400 to 600 MILLION sperms are
deposited at cervical opening during ejaculation.
– Some sperm are held up by the folds of the cervix and
are gradually released into the cervical canal; this
gradual release increases the chances of fertilization.
– Most human sperms do not survive longer than 48 hours
in the female genital tract.
• Only about 200 sperms reach the fertilization site;
most degenerate and are absorbed by the female
genital tract.
Summary of fertilization

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The primary sex-determining gene in mammals is
on the Y chromosome

• The presence of a Y chromosome results in the somatic cells of the


embryo's gonads developing into testes rather than into ovaries.
• The testes secrete Mullerian-inhibiting substance, which suppresses
further female development.
• The hormone testosterone stimulates the development of male
reproductive organs.
• Specification of a gonad as a testis is controlled by a single gene on the
Y chromosome.
• The sex-determining region of the Y
chromosome (SRY in humans and Sry in
mice), which was formly known as testis-
determining factor.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


The primary sex-determining gene in mammals is
on the Y chromosome
Early Gonad Development
• Before 6-7 weeks of
development, the gonad is
indifferent: neither male nor
female.
• It develops from the same tissue
as the kidneys and adrenal
glands.
• Also developing by this time: 2
sets of ducts that will eventually
lead to the outside world.
– Wolffian ducts = male
– Mullerian ducts = female
The primary sex-determining gene in mammals is
on the Y chromosome
Sex reversal in humans due to chromosomal exchange.

At meiosis in male germ cells. the X and Y


chromosomes pair up (center panel) and

There is crossing over of the distal region


(blue cross), which does not affect sexual
development (left panel).

On rare occasions, crossing over involves a


larger segment that indudes the SRY gene
(red cross), so that the X chromosome now
carries this male-determining gene (right
panel).

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


The primary sex-determining gene in mammals is
on the Y chromosome
Klinefelter Syndrome: 47,XXY

• Occurs about 1 per 500 male births. It is the most


common type of sex chromosome variant.
• The presence of the Y chromosome causes a
47,XXY person to be male, both externally and
internally, because the testes are formed.
• Root symptom: small testes, leading to low
testosterone levels. Most, but not all, are sterile.
• At puberty, reduced facial and body hair, broader
hips, breast development.
• 47,XXY children tend to be taller, less physically
strong and coordinated, and more quiet and shyer
than their peers. Some language and learning 46,XX males, with the SRY
problems are common: often slow to learn to speak gene on the X, have the
and read. Klinefelter appearance.
• Testosterone replacement therapy helps with some
of the physical symptoms. Speech therapy and
educational services also help.
The primary sex-determining gene in mammals is
on the Y chromosome
Turner Syndrome: 45,X
• Only one X chromosome, sometimes called XO. Since
there is no Y chromosome, the primary gonad is the
ovary, and 45,X people are female.
• About 1 in 2500 live female births.
– 10% of all spontaneous abortions (miscarriages)
are due to Turner syndrome; about 98% of all
Turner’s embryos die before birth
• Ovaries completely non-functional, so 45,X women are
sterile, with no production of sex hormones and
development of secondary sexual characteristics at
puberty.
• Some characteristic physical abnormalities: short
stature, low hairline, webbed skin at neck. Kidney and
circulatory system problems
• Often have problems with spatial reasoning and You need 2 X chromosomes for
mathematics. Also social difficulties: inability to proper ovarian development.
understand others’ emotions. 46,XY females (non-functional
SRYgene) resemble Turner’s
• Can be treated with growth hormone and estrogen.
The primary sex-determining gene in mammals is
on the Y chromosome
47,XYY
• About 1 in 1000 live male births. Most XYY’s are never
detected: a very mild condition.
• since 1960, newly discovered chromosome variants aren’t given
the discoverer’s name
• It was once thought to create hyper-aggressive males with a
tendency towards criminal behavior.
– Richard Speck, the killer of eight student nurses in 1966,
pretended (falsely) to be an XYY to obtain leniency.
– A 1968 letter to the Lancet claimed that XYY men were in
prison at a rate "25-60 times as high as the prevalence in
the general population”, based on finding 2 XYY’s.
– the plot of Aliens 3 involves a prison planet for XYY’s. 1970’s British TV series:
• XYY’s are generally normal in appearance, but with average He had an extra Y,
height about 7 cm above expected and normal build. Perhaps which made him a
acne is more common than average, but this is disputed. macho criminal!
• They are often more physically active, somewhat delayed in
emotional maturity, and have a slight increase in learning and
speech problems.
• Fertile, normal sex drive, very rarely pass 2 Y’s to sons.
Development of the gonads and related structures in
mammals
Top panel:
•Early in development, there is no difference
between males and females in the structures that
give rise to the gonads and related organs.

•The future gonads lie adjacent to the


mesonephros, which are embryonic kidneys that
are not functional in adult mammals. (The true
kidney develops from the metanephros. from
which the ureter carries urine to the bladder.)

•Two sets of ducts are present: the Wolffian ducts,


which are associated with the mesonephros. and
the Mullerian ducts. Both ducts enter the cloaca.

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Development of the gonads and related structures in
mammals

Bottom left panel:


•After testes develop in the male. their secretion of
Mullerian-inhibiting substance results in
degeneration of the Mullerian duct by programmed
cell death, whereas the Wolffian duct becomes the
vas deferens, carrying sperm from the testis.
Bottom right panel:
•In females, the Wolffian duct disappears, also by
programmed cell death, and the Mullerian duct
becomes the oviduct. The uterus forms at the end
of the Mullerian ducts. After Higgins, 5.J., eta!.: 1989.

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Development of the genitalia in humans

At an early embryonic stage, the genitalia


are the same in males and females (top
panel).

After testis formation in males, the phallus


and the genital fold give rise to the penis,
whereas in females they give rise to the
clitoris and the labia minus.

The genital swelling forms the scrotum in


males and the labia majus in females

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The primary sex determining in Drosophila

• The primary sex determining signal in Drosophila is the


number of X chromosomes, and is cell autonomous
• Like mammals, fruit flies have tvvo unequally sized sex
chromosomes, X and y, and males are XY and females
XX.
• But these similarities are misleading.
• In flies, sex is not determined by the presence of a Y
chromosome, but by the number of X chromosomes.
Thus, XXY flies are female and X flies are male.
• The chromosomal composition of each somatic cell
The left side of the fly is composed
determines its sexual development. of XX cells and develops as a
female.
• This is beautifully illustrated by the creation of genetic
whereas the right side is composed
mosaics in which the left side of the animal is XX and the of X cells and develops as a male.
right side X: the two halves develop as female and male, The male fly has smaller wings, a
respectively special structure, the sex comb, on
its first pair of legs and different
genitalia at the end of the abdomen
(not shown).
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Outline of the sex determination pathway in
Drosophila.

• The number of X chromosomes is the primary sex-determining signal, and in


females the presence of two X chromosomes activates the gene Sexlethal
(Sxl).
• This produces Sex-lethal protein, whereas no Sex-lethal protein is made in
males, who have only one X chromosome.
• The activilty of Sex-lethal is transduced via the transformer gene (tra) and
causes sex-specific splicing of double Sex RNA (dsxf), such that the cells
follow a female developmental pathway.
• In the absence of Sex-lethal protein, the splicing of double sex RNA to give
dsxm RNA leads to male development.

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Production of Sex-lethal protein in Drosophila sex
determination

• When two X chromosome are present, the early establishment promoter (Pe) of the
Sexlethol (Sxl) gene is activated at the syncytial blastoderm stage in future
females, but not in males. This result in the production of Sxl protein.
• Later, at the blastoderm stage, the maintenance promoter (Pm) of Sxl becomes
active in both females and males, and Pe is turned off.
• The Sxl RNA is only correctly spliced
if Sxl protein is already present which
is only in females.
• A positive feedback loop for Sxl
protein production is thus established
in females. The continued presence
of Sxl protein initiates a cascade of
gene activity leading to female
development.
• If no Sxl protein is present, male
development ensues.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Somatic sexual development in Caenorhabditis is
determined by the number of X chromosomes
Hermaphrodite and male C. elegans
• In the nematode C. elegans, the two sexes are hermphrodite (essentially a
• modified female) and male.
• Hermaphrodites produce a limited amount of sperm early in development with
the remainder of the genu cells developing into oocytes.
• Sex in C. elegans (and other nematodes) is determined by the number of X
chromosomes: the hermaphrodite (XX) has two X chromosomes, whereas the
presence of just one X chromosome leads to development as a male (XO).
• The primary sex signal in C. elegans
acts on the gene XO lethal (xol-l ).
• With two X chromosomes, xol-1
expression is low, resulting in the
development of a hermaphrodite
• xoI-1 is repressed by the SEX-1 protein,
which is encoded on the X chromosome

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Somatic sexual development in Caenorhabditis is
determined by the number of X chromosomes
Hermaphrodite and male C. elegans
• A cascade of gene activity converts the level of xol-l expression into the
somatic sexual phenotype.
• Genes involved include those for nuclear proteins, such as SDC-1 and for a
secreted protein Hermaphrodite-1 (HER-1).
• At the end of the cascade is the gene transformer-1 (tra-1), which encodes a
transcription factor.
• Expression of transformer-1 protein is both necessary and sufficient to direct
all aspects of hermaphrodite (XX) somatic cell development

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Most flowering plants are hermaphrodites, but
some produce unisexual flowers

• The flowers of angiosperms share a common organization in which


the four types of floral organs are arranged in concentric whorls.
• The two inner whorls are the sexual organs-the stamens and carpel.
• Sepals and petals in the outer whorls are not sexual organs, but may
serve to attract pollinators.
• Stamens produce pollen, which contains the male gametes
corresponding to the sperm of animals.
• The female reproductive structure of flowers are the carpels, which
are either free, or are fused to form a compound ovary.
• Carpels are the site of ovule formation and each ovule produces an
egg cell Most flowering plants are hermaphrodites, bearing flowers
with functional male and female sexual organs.
• However, not all flowering plants are of this type. In about 10% of
flowering plants, flowers of just one sex are produced.
• Flowers of different sexes may occur on the same plant. or be confined to different plants
• The plant hormone gibberellic acid may be involved in sex determination, as differences in
gibberellin concentration are associated with the different sexual organs
Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press
Germ-cell sex determination can depend both on cell
signals and genetic constitution

• In male embryos, diploid germ cells divide mitotically for


some time in the genital ridge.
• But then also stop dividing, becoming arrested in the G1
phase of the cell cycle.
• They start dividing again after birth and enter meiosis
some 7 to 8 days after birth.
• Migrating germ cells, whether xx or xy. enter meiotic
prophase and start developing as oocytes unless they
enter a testis.
• In the testis. the germ cells receive an inhibitory signal
that blocks mitotic division and prevent them entering
meiotic prophase

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Germ-cell sex determination can depend both
on cell signals and genetic constitution

• All mouse germ cells that enter meiosis before birth develop as eggs,
whereas those not entering meiosis until after birth develop as sperm.
• Germ cells, whether XX or XY that fail to enter the genital ridge and instead
end up in adjacent tissues such as the emblyonic adrenal gland or
mesonephros. enter meiosis and begin developing as oocytes in both male
and female embryos.
• In XX/XY chimeras. XX germ cells that are surrounded by testis cells develop
along the spermatogenesis pathway.
• However, the later development of germ cells that develop in these
inappropriate sites is abnormal.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Germ-cell sex determination can depend both
on cell signals and genetic constitution

• In Drosophila, the difference in the behavior of XY and XX germ cells


depends initially on the number of X chromosomes, as in somatic cells.
• The Sex-lethal gene again plays an important role, although other elements
in the sex-determination pathway may differ from those in somatic cells.
• As in mammals, both chromosomal constitution and cell interactions are
involved in the development of germ cell sexual phenotype.
• Transplantation of genetically marked pole cells into a Drosophila embryo
of the opposite sex shows that male XY germ cells in a female embryo
become integrated into the ovary and begin to develop as sperm;
• That is. their behavior is autonomous with respect to their genetic
constitution.
• By contrast. XX germ cells in a testis develop as sperm, showing a role for
environmental signals. In neither case, however. are functional sperm
produced.
Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press
Germ-cell sex determination can depend both
on cell signals and genetic constitution

• In C. elegans. entry of germ cells into meiosis from the third larval stage onward
is controlled by the distal tip signal.
• In the presence of this signal, the cells proliferate, but as they move away from it.
they enter meiosis and develop as sperm.
• In the hermaphrodite gonad, all the cells that are initially outside the range of the
distal tip signal develop as sperm, but cells that later leave the proliferative zone
and enter meiosis develop as oocytes.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Mechanisms of dosage compensation

• In mammals, Drosophila, and C elegons there are two X chromosomes in one


sex and only one in the other.
• Mammals inactivate one of the X chromosomes in females; in Drosophilo males,
there is an increase in transcription from the single X chromosome; and in C
elegons there is a decrease in transcription from the X chromosomes in
hermaphrodites.
• The result of these different
dosage compensation
mechanisms is that the level of X
chromosome transcripts is
approximately the same in males
and females.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Mechanisms of dosage compensation

• Mammals. such as mice and humans achieve dosage


compensation in female by inactivating one of the X
chromosomes in each cell after the blastocyst has
implanted in the uterine wall.
• Once X chromosome has been inactivated in an
embryonic cell, this chromosome is maintained in the
inactive state in all the resulting somatic cells and
persists throughout the life of the organisms.
• The inactivated X chromosome is replicated at each
cell division but remains transcriptionally inactive.
• The inactivated X chromosome is visible in human
cells the Barr body.

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Mechanisms of dosage compensation
Inactivation of X chromosome

• The mosaic effect of X inactivation of X-linked phenotype is sometimes visible


in the coats of female mammals.
• X-inactivation is dependent on the small region of the X chromosome
inactivating centre
• Contains a pair of overlapping genes for two non-coding RNA Xist and Tsix,
whose competing activities regulate inactivation.
• Before inactivation, both RNAs are transcribed at low levels from both X
chromosomes
• Xist expression then dramatically increases on one or other of the X
chromosome and ceases on the other.
• Xist involve in blocking transcription including
Tsix and inactivate chromosome
• On the chromosome that is not inactivated Tsix
remains active for little time but soon after
inactivation is completed both Xist and Tsix are
switch off.
Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press
Summary

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press


Summary

Principles of Development 4e Wolpert/Tickle Copyright © 2011 by Oxford University Press

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