Human Fertility
Lecture 1. Germ cell development and sexual differentiation
Sexual determination and sexual differentiation
In humans, the sex chromosomes are XX for females and XY for males. However, this is not the case
for all organisms. For example, in birds the opposite is true: XY for females and XX for males. In
insects only the females have two sex chromosomes (XX, so diploid) and the males only have one (XO,
so haploid). In other cases, for examples for amphibians, the sexual determination depends on
temperature of the environment.
Sry gene
The Sry gene is located on the Y chromosome and encodes for the SRY (Sex-determining Region Y)
protein. In mammals, SRY is responsible for the initiation of male sexual determination. In every case
that Sry gene is present, the embryo is going to develop as a male. So, when the sex chromosomes
are XX but Sry is present, the embryo will develop as a male. When the sex chromosomes are XY but
Sry is absent, the embryo will develop as female.
Sexual determination (genetic gender) is the designation for the development stage towards either
male or female. It starts at fertilization (genotypic differentiation). Sry genes are already transcribed
before implantation. The XY embryos will develop more rapidly than XX embryos. Approximately 6-7
weeks after fertilization, primordial germ cells (PGCs) migration takes place during which the PGCs are
distributed throughout the embryo. This is the start of phenotypic differentiation. Gonads are
developing and there is differentiation of the external genetalia. Sexual differentiation is the process
of development of the sex differences between males and females from an undifferentiated zygote. It
is the pathway towards the development of the phenotype. The most important sexual differentiation
starts at puberty. Sexual determination is more related to genetics and sexual differentiation is
related to hormones. Hormones depend on genetics, so sexual differentiation depends on sexual
determination.
Development of germline cells
After implantation, the DNA of the cells is almost
completely demethylated. At week 2, the first
primordial germ cells are formed. After this,
there is a second wave of complete
demethylation. Gametes derive from the
primordial germ cells (PGCs) that are formed
during the second week. After formation of
PGCs, they move through the embryo. After a
period of development that is common to both
sexes, germ cells undergo sex-specific processes
determined by the ovarian. The PGCs cannot
develop by themselves but need support cells. In the testes, these supporting cells are the Sertoli
cells. In the ovaries, these are the granulosa cells.
,In the beginning, there is the blastocyst that consists of the inner cell mass and the trophoblast. The
trophoblast will eventually give rise to the placenta. The inner cell mass will give rise to the embryo.
At one time in the development, the primordial germ cells are going to move to the placenta to avoid
changes in the epigenetics. At 6-7 weeks of embryo development, the PGSs migrates back to the
embryo. They eventually invade the primitive gonad (sex gland) and together with epithelial cells
form primitive sex cords. The gonads will not develop if the PGC fail to reach the genital ridge. Once
arrived in the genital ridges the PGCs are reprogrammed and express new sets of genes, global DNA
demethylation, chromatin remodelling and reactivation of both X chromosomes. The PGCs are now
called gonocytes and loose the capacity to migrate. After 2-3 mitotic divisions they become pre-
meiotic. In male embryo, this process is reversed and the future spermatogonia go into mitotic arrest
until the start of puberty. In female embryo, meiosis does start but is arrested in the meiose I phase
until the start of puberty.
When primordial germ cells are misdirected and survive, they may develop into teratomas.
Teratomas are tumors of disputed origin that often contain a variety of tissues, such as bone, hair,
muscle, gut epithelia, and others.
Genes involved in sex determination and development
During embryo development, a lot of genes are involved. Here the most important genes are
discussed that are involved in early development.
WT1 (male & female): transcription factor, no gonads will develop if WT1 is mutated.
SF-1 (male & female): transcription factor important for males, no gonads will develop if SF-1
is mutated. Leydig cells express SF-1 to regulate transcription of testosterone. Testosterone
stimulates differentiation of the Wolffian duct.
SOX9 (male): autosomal gene, transcription factor that induces the primitive sex cords. It is
also involved in the differentiation of Sertoli cells.
SRY (male): stimulates the expression of anti-Müller hormone (AMH). AMH stimulates
degeneration of the Müller duct in males.
DAX1 (female): gene is located on X-chromosome of female and male and encodes nuclear
hormone receptor. Important for female sexual differentiation. overexpression of DAX1 in XY-
man results in poor development of the gonads and female sexual differentiation. In females,
SF-1 and WT1 activate the DAX-1 gene. DAX-1 is important for the development of the ovary.
Wnt4 (female): autosomal gene, expressed in female gonads. WNT4 represses the
differentiation of Leydig cells, therefore, it represses the production of t estosterone. In
female Wnt4-/- mice, ovaries, Müller ducts and Wolffian ducts are absent.
, The Y-chromosome
The difference between the X- and Y-chromosome is that the Y-chromosome contains the SRY gene
and it is shorter in length. The Y-chromosome has different regions. One part is exactly the same as
the X-chromosome. Y chromosomes is shorter than its ancestor version.
The pseudoautosomal regions (PAR) are where the Y chromosome pairs and exchanges genetic
material with the PAR of the X chromosome during male meiosis. Consequently, genes located within
the PAR are inherited in the same manner as autosomal genes. The PAR represents 5% of the entire
chromosome. Most of the length of the Y-chromosome (95%) is made up by the Male Specific Region
of the Y (MSY). This region is gene-poor and will not undergo meiotic recombination with the X-
chromosome. The function of most of these genes are limited to spermatogenesis. MSY includes
euchromatic and heterochromatic sequences of the chromosome. It is important for the sex
determination and male fertility.
In the Y-chromosome, there are two types of genes:
- Class 1 genes: “housekeeping” genes with a homologous gene in the X-chromosome
- Class 2 genes: involved in spermatogenesis, often multi-copy genes
o Repeats, palindromes, duplications
Numerical genetic anomalies
Syndrome Symptoms
XX True hermaphrodite Phenotype is female. However, both testicular and ovarian
tissue are present and sometimes ovotestis. Hypertrophy of
clitoris.
XX Female Internal female genitalia, but masculinized external
pseudohermaphroditism genitalia. Cause: excessive production of androgenic
hormones or from hormonal treatment during pregnancy.
XY Male pseudohermafroditism hypoplasia of phallus. Cause: inadequate hormone
production by the fetal testes.
XY Testicular Male with female phenotype. Testes produce testosterone,
Feminization/Androgen but have a deficiency in the receptors.
insensitivity syndrome
XO Turner syndrome
XXY Klinefelter syndrome
XYY XYY/Jacobs syndrome Aggressive behavior
XXX Triple X syndrome
Lecture 1. Germ cell development and sexual differentiation
Sexual determination and sexual differentiation
In humans, the sex chromosomes are XX for females and XY for males. However, this is not the case
for all organisms. For example, in birds the opposite is true: XY for females and XX for males. In
insects only the females have two sex chromosomes (XX, so diploid) and the males only have one (XO,
so haploid). In other cases, for examples for amphibians, the sexual determination depends on
temperature of the environment.
Sry gene
The Sry gene is located on the Y chromosome and encodes for the SRY (Sex-determining Region Y)
protein. In mammals, SRY is responsible for the initiation of male sexual determination. In every case
that Sry gene is present, the embryo is going to develop as a male. So, when the sex chromosomes
are XX but Sry is present, the embryo will develop as a male. When the sex chromosomes are XY but
Sry is absent, the embryo will develop as female.
Sexual determination (genetic gender) is the designation for the development stage towards either
male or female. It starts at fertilization (genotypic differentiation). Sry genes are already transcribed
before implantation. The XY embryos will develop more rapidly than XX embryos. Approximately 6-7
weeks after fertilization, primordial germ cells (PGCs) migration takes place during which the PGCs are
distributed throughout the embryo. This is the start of phenotypic differentiation. Gonads are
developing and there is differentiation of the external genetalia. Sexual differentiation is the process
of development of the sex differences between males and females from an undifferentiated zygote. It
is the pathway towards the development of the phenotype. The most important sexual differentiation
starts at puberty. Sexual determination is more related to genetics and sexual differentiation is
related to hormones. Hormones depend on genetics, so sexual differentiation depends on sexual
determination.
Development of germline cells
After implantation, the DNA of the cells is almost
completely demethylated. At week 2, the first
primordial germ cells are formed. After this,
there is a second wave of complete
demethylation. Gametes derive from the
primordial germ cells (PGCs) that are formed
during the second week. After formation of
PGCs, they move through the embryo. After a
period of development that is common to both
sexes, germ cells undergo sex-specific processes
determined by the ovarian. The PGCs cannot
develop by themselves but need support cells. In the testes, these supporting cells are the Sertoli
cells. In the ovaries, these are the granulosa cells.
,In the beginning, there is the blastocyst that consists of the inner cell mass and the trophoblast. The
trophoblast will eventually give rise to the placenta. The inner cell mass will give rise to the embryo.
At one time in the development, the primordial germ cells are going to move to the placenta to avoid
changes in the epigenetics. At 6-7 weeks of embryo development, the PGSs migrates back to the
embryo. They eventually invade the primitive gonad (sex gland) and together with epithelial cells
form primitive sex cords. The gonads will not develop if the PGC fail to reach the genital ridge. Once
arrived in the genital ridges the PGCs are reprogrammed and express new sets of genes, global DNA
demethylation, chromatin remodelling and reactivation of both X chromosomes. The PGCs are now
called gonocytes and loose the capacity to migrate. After 2-3 mitotic divisions they become pre-
meiotic. In male embryo, this process is reversed and the future spermatogonia go into mitotic arrest
until the start of puberty. In female embryo, meiosis does start but is arrested in the meiose I phase
until the start of puberty.
When primordial germ cells are misdirected and survive, they may develop into teratomas.
Teratomas are tumors of disputed origin that often contain a variety of tissues, such as bone, hair,
muscle, gut epithelia, and others.
Genes involved in sex determination and development
During embryo development, a lot of genes are involved. Here the most important genes are
discussed that are involved in early development.
WT1 (male & female): transcription factor, no gonads will develop if WT1 is mutated.
SF-1 (male & female): transcription factor important for males, no gonads will develop if SF-1
is mutated. Leydig cells express SF-1 to regulate transcription of testosterone. Testosterone
stimulates differentiation of the Wolffian duct.
SOX9 (male): autosomal gene, transcription factor that induces the primitive sex cords. It is
also involved in the differentiation of Sertoli cells.
SRY (male): stimulates the expression of anti-Müller hormone (AMH). AMH stimulates
degeneration of the Müller duct in males.
DAX1 (female): gene is located on X-chromosome of female and male and encodes nuclear
hormone receptor. Important for female sexual differentiation. overexpression of DAX1 in XY-
man results in poor development of the gonads and female sexual differentiation. In females,
SF-1 and WT1 activate the DAX-1 gene. DAX-1 is important for the development of the ovary.
Wnt4 (female): autosomal gene, expressed in female gonads. WNT4 represses the
differentiation of Leydig cells, therefore, it represses the production of t estosterone. In
female Wnt4-/- mice, ovaries, Müller ducts and Wolffian ducts are absent.
, The Y-chromosome
The difference between the X- and Y-chromosome is that the Y-chromosome contains the SRY gene
and it is shorter in length. The Y-chromosome has different regions. One part is exactly the same as
the X-chromosome. Y chromosomes is shorter than its ancestor version.
The pseudoautosomal regions (PAR) are where the Y chromosome pairs and exchanges genetic
material with the PAR of the X chromosome during male meiosis. Consequently, genes located within
the PAR are inherited in the same manner as autosomal genes. The PAR represents 5% of the entire
chromosome. Most of the length of the Y-chromosome (95%) is made up by the Male Specific Region
of the Y (MSY). This region is gene-poor and will not undergo meiotic recombination with the X-
chromosome. The function of most of these genes are limited to spermatogenesis. MSY includes
euchromatic and heterochromatic sequences of the chromosome. It is important for the sex
determination and male fertility.
In the Y-chromosome, there are two types of genes:
- Class 1 genes: “housekeeping” genes with a homologous gene in the X-chromosome
- Class 2 genes: involved in spermatogenesis, often multi-copy genes
o Repeats, palindromes, duplications
Numerical genetic anomalies
Syndrome Symptoms
XX True hermaphrodite Phenotype is female. However, both testicular and ovarian
tissue are present and sometimes ovotestis. Hypertrophy of
clitoris.
XX Female Internal female genitalia, but masculinized external
pseudohermaphroditism genitalia. Cause: excessive production of androgenic
hormones or from hormonal treatment during pregnancy.
XY Male pseudohermafroditism hypoplasia of phallus. Cause: inadequate hormone
production by the fetal testes.
XY Testicular Male with female phenotype. Testes produce testosterone,
Feminization/Androgen but have a deficiency in the receptors.
insensitivity syndrome
XO Turner syndrome
XXY Klinefelter syndrome
XYY XYY/Jacobs syndrome Aggressive behavior
XXX Triple X syndrome
