The embryonic gonad is capable of becoming either an ovary or testis.
Ovarian development will result without specific signals from the Y chromosomal
SRY gene, also known as the testis determining factor. An embryonic gonad
needs to express a functional SRY gene in order to become a testis.
The SRY gene, also known as the testis determining factor, can be mutated
or it can be transferred to an X chromosome. If an XY embryo lacks a functional
SRY gene, a normal (although infertile) female will develop. If an XX
embryo possesses an SRY gene, a normal male will develop. There are genes
which apparently act in gender differentiation downstream of the function
of the SRY gene. Mutations or duplications in these genes can cause sex
reversal (usually in males but partial sex reversal is also possible in
females), regardless of chromosomal gender or the presence of SRY. Some
mutations produce pseudohermaphrodites.
The sex-determining SRY gene is a member of the SOX gene family. SOX genes
have been conserved in coleomates and Drosophila. DSox14 is similar to
SRY (Sparkes, 2001). In vertebrates, a number of SOX genes can expressed
in the gonads including Sox 5, 6, 8, 9, 17, 20, 23, 24, and 30. A duplication
of a SOX gene, probably the ancestor of SOX3, gave rise to a gene named
SRY which is not only expressed in the testis, but is the testis determining
factor located on the Y chromosome of therian mammals (placentals and
marsupials). To date, the SRY gene has not been identified in monotremes.
It is present in marsupials, although it has not been demonstrated to
function in sex determination. Genes other than SRY can determine gender,
given that some placental mammals lack SRY and that the majority human
XY females do not have mutations in the SRY gene (Pask, 2000). By the
origin of the mammalian lineage, three additional genes (Sry, Sox15, and
Sox30) had evolved in the SOX family (Koopman, 2004). SRY lacks introns,
as does SOX3, the gene to which it is most similar and from which it may
SRY is located on Yp11 and is the tdf gene-the testes determining factor.
An XY individual with a mutation in SRY can develop as a normal female
although typically there are no menses (in one case, menstrual cycles
occurred but there were no follicles). Some of the mutations of SRY which
lead to the development of XY females are known to interfere with the
protein's ability to bend DNA rather than bind DNA (Koopman, 1999). A
fifth of human XY females possess mutations in the HMG box of SRY (Nagai,
2001). In mice, such females can be fertile but the ovaries fail early
in life. An XX individual with the SRY gene translocated to one of the
X chromosomes develops as a male. SRY is sufficient to initiate male development
in mice which are chromosomally female (XX) (Holmes, 1996). Mutations
in the SRY gene during development can produce true hermaphrodites: individuals
with both male and female tissue. SRY interacts with a number of autosomal
genes which can determine the effects of mutations. A father with a mutant
SRY gene may be male, but can produce an XY daughter due to differences
in the genetic background of these autosomal genes (OMIM).
SRY is most highly expressed in the genital ridge in the 6 week male prior
to testis formation human embryo and is limited to the testis in adult
males (Magararit, 1998). SRY initiates the differentiation and production
of Sertoli cells, migration of cells from the mesonephros into the testis,
and development of male pattern of blood vessels (Tilmann, 2002). The
early embryonic gonads are capable of differentiating in male or female
specific pathways. SRY causes the development of Sertoli cells from cells
which would otherwise have formed follicular cells (although the presence
of PCGs is also required for the formation of follicular cells) (Tilmann,
Interestingly, SRY has been modified or lost in some mammalian groups.
An intron has been inserted in the SRY gene of dasyurid marsupials, apparently
without altering its function (O'Neill, 1998). Mole voles do not use SRY
or SOX9 to determine gender. There must be an additional testis determining
factor as yet unknown in them (Baumstark, 2001). Males and females of
the rodent Tokudaia osimensis have the same karyotype, lacking a Y chromosome.
This species does not involve the gene Sry in sex determination as does
the rest of its subfamily (Murniae, Family Muridae). Similarly, two species
of the rodent genus Ellobius do not use Sry in sex determination, have
identical karyotypes in males and females, and thus are unlike the other
members of their subfamily (Arvicolinae, Family Muridae) (Soullier, 1998;
OTHER GENES INVOLVED IN SEXUAL DIFFERENTIATION
Reptilian homologs of AMH, DAX1, SF1, SOX9, and WT1 seem to function similarly
to those proteins in mammals (Pleau, 1999; Shimada, 1998). The enzyme
3ß-hydroxysteroid dehydrogenase-5-ene-4-ene isomerase (3ß
HSD) is important in steroid synthesis and has a temperature sensitive
activity (Pleau, 1999). The activity of aromatase which converts androgen
to estrogen seems to be an important feature of temperature sensitive
sex determination in reptiles. Aromatase is also temperature sensitive.
Both these enzymes vary in their activity at male vs. female-producing
incubation temperatures (Pleau, 1999).
A number of genes determine the differentiation of reproductive tissues
into male or female specific patterns. Mutations in these genes can cause
sex reversal or the development of some type of intersex phenotype. Intersex
individuals have been described in goats, llamas, sheep, pigs, pandas,
dogs, cats, raccoon dogs, whales, moles, rabbits, kangaroos, wallabies,
opossums, horses, mice, voles, lemmings, and humans (Vaiman, 2000). The
females of several species of the mole genus Talpa possess ovotestes,
gonads with both ovarian and testicular tissue (Barrionuevo, 2004).
A number of genes are known to be involved in the differentiation
of gonads. SF1 and WT1 are required for the genital ridge to become a
bipotential gonad. SRY and SOX9 are required for this gonad to become
a testis, after which point SF1 is required for testosterone production
(and thus the maturation of male structures) and SF1 and AMH are required
for the regression of Muellerian ducts. DAX1 is required for the production
of the ovary and SF1 promotes the production of follicular cells (Ramikissoon,
SOX9 mutations cause feminization of XY individuals and autosomal sex
reversal (Jordan, 2001, Vaiman, 2000) and may be a vestige of an older
dosage-dependent mechanism for sex determination which predated the use
of SRY as the testis determining factor (Foster, 1994). In birds and mammals,
SOX9 is preferentially expressed in males and functions in testis differentiation.
In frogs, it is expressed in both genders, seemingly involved in the development
of both ovaries and testes (Takase, 2000).
SOX9 is expressed in the brain, heart, and testes. Sox9 is needed for
the endochondral skull elements formed by cranial neural crest cells but
not for intermembranous bone and that formed from mesoderm. Sox9 is involved
in both chondrogenesis and sex determination. Mutations cause skeletal
dysplasia (Mori-Akiyama, 2003; OMIM). SOX9 is essential for chondrocyte
development and targets the enhancer of chondrocyte specific genes, such
as collagen Col2a1 (Lefebvre, 1997/8).
The DAZ genes on the Y chromosome are important for fertility and deletions
here are a common cause of male infertility. This Y specific chromosome
cluster is thought to be derived from and ancestral gene on human chromosome
3 (DAZL) which is required for both male and female fertility in other
organisms. Another autosomal gene (BOULE) may be the ancestor of DAZL
and it is homologous to genes which regulate meiosis in invertebrates.
BOULE was present in early bilateran animals, DAZL evolved early in the
vertebrate lineage, and the Y-specific DAZ cluster evolved since the divergence
of new world monkeys and human lineages (Xu, 2001).
There is an X-linked gene DAX-1 which, when present in two copies, can
cause XY individuals with SRY to develop as females. It is a nuclear hormone
receptor that binds to retinoic acid and regulates transcription. DAX-1
is not required for normal male development (Zanaria, 1994). DAX and SRY
are thus antagonistic in their function. (Jordan, 2001). DAX inhibits
Sertoli cell development (Clarkson, 2002).
Mutations in FGF9 in mice can cause a number of defects ranging from the
underdevelopment of testes to sex reversal (in addition to effects in
other tissues such as underdevelopment of lungs) (Colvin, 2001).
Mammalian WT1 can produce 24 different proteins through alternate splicing,
alternate translational initiation sites, and RNA editing (Clarkson, 2002).
WT1 upregulates SRY expression and can also activate BCL2, CDKN1A, and
DAX1. WT1 mutations can cause complete sex reversal. (Clarkson, 2002).
WT1 and SF1 are upstream of SRY (Magararit, 1998). WT1 possess four zinc
finger domains and mutations are involved in four types of disorders:
Wilms tumor, WAGR syndrome, Frasier Syndrome, and Denys-Drash Syndrome.
All of these syndromes may include some aspects of sex reversal (Vaiman,
Wt1 is required for the production of both kidneys and gonads (Tilmann,
2002). Wnt family members act through Frizzled receptors (Jordan, 2001).
Wnt-4 expression is maintained in developing ovaries but not developing
testes. XX mice without Wnt-4 masculinization and persistence of rudimentary
male ducts, and degeneration of female ducts. Overexpression of Wnt-4
in XY individuals results in female development (Jordan, 2001).
SF-1 is a orphan nuclear hormone receptor. Mutations can result in sex
reversal and agenesis of the adrenal glands and gonads. Sex reversal can
occur in heterozygous humans (Vaiman, 2000; (Jordan, 2001). SF1 functions
upstream of SRY (Magararit, 1998). Some turtles have a gender specific
SF1 expression pattern similar to mammals. SF1 has a similar pattern of
expression in marsupials and placental mammals. It is involved in the
development of the adrenal glands, anterior pituitary, and hypothalamus.
It also regulates cytochrome 450 genes which are involved in steroid metabolism
in ovaries and testes (Whitworth, 2001).
In mammals, the first step in sex determination is the differentiation
of the gonads controlled by genes followed by a second step of phenotypic
changes induced by hormones. Anti-Muellerian hormone is a member of the
TGFß family which is required for male development (without which
they develop as pseudohermaphrodites). Females exposed to AMH undergo
partial sex reversal. Four transcription factors are known to bind to
the AMH promoter: SF-1, WT1, SOX-9, and GATA-4 (Vaiman, 2000). Mullerian
inhibiting substance is a member of the TGFß family which is expressed
by Sertoli cells in developing testis (Tilmann, 2002).
In birds, androgens and Anti-Muellerian hormone are required for testicular
development while estrogen is important for ovarian development. Sox9
may be the transcription factor which initiates the transcription of male
genes and AMH (Shimada, 1998).
ATRX is a member of the helicase superfamily that is only found on the
X chromosome. Mutations in humans can cause thalassemia, mental retardation,
and sex reversal. An ATRY gene (on the Y chromosome) is known in marsupials
and it expressed in the testes. ATRX is involved in gonadal development
downstream of SRY, SOX9, and AMH. ATRX is not expressed in the marsupial
testis (Pask, 2000).
M33, a homolog of Drosophila polycomb, can also cause sex reversal (Tilmann,