The SRY gene encodes the testis-determining factor (TDF) protein that initiates male development in mammals. SRY was first discovered in 1990 in mice and humans. It is located on the Y chromosome and contains a high mobility group (HMG) box DNA-binding domain. SRY acts as a transcription factor that binds to DNA and activates genes involved in testis formation, such as SOX9. Mutations in SRY can cause disorders of sex development like Swyer syndrome in which XY individuals develop as females. Additionally, the presence of SRY in XX individuals results in XX male syndrome. Recent research also links SRY to increased vulnerability of dopamine neurons and risk of Parkinson's disease in males.
2. In 1990, the Sry and SRY genes were discovered on the mouse and human Y chromosome,
respectively (Gubbay et al., 1990; Sinclair et al., 1990). Since then, no molecular mechanism of
SRY action in testis determination had been proven, despite the proposal of several
differentmodels; SRY activates gene expression through its consensus binding site (A/T)
AACAAT (Dubin and Ostrer, 1994), represses a putative suppressor of a testis-promoting factor
(McElreavey et al., 1993), functions as an architectural factor by bending DNA (Pontiggia et al.,
1994), and is involved in pre-mRNA splicing (Ohe et al., 2002).
SRY may be divided into three different regions; the N-terminal domain (N-TD), HMG box and
C-terminal domain (C-TD). The N-TD is some 30–60 amino acids in length, and the C-TD also
varies with mammalian species. However, mSRY has an unusual structure in comparison with
other SRY proteins. Since its N-TD contains only 2 amino acids, the HMG box is essentially N-
terminal. It also has a glutamine (Q)-rich domain in the C-TD, which is derived from degenerate
CAG repeats. Moreover, there is a “bridge domain” situated between the HMG box and the Q-rich
domain. Sry contains no introns in most mammalian species, except for some marsupials. The
mouse Sry (mSry) gene is flanked by a set of large inverted repeats (Hacker et al., 1995). In
addition to the linear Sry mRNA, the gene generates a circular transcript, which is detected only
in the adult testis. This arises from a long transcript that includes the inverted repeats, which pairs
and generates a stem loop structure from which the circle is formed via splicing (Capel et al.,
1993). No inverted repeat has been identified in other mammalian SRY genomic regions.
Moreover, a comparative genome analysis shows that there are several conserved regions upstream
of human, bovine, pig and goat SRY, but not of mouse Sry (Ross et al., 2008).
Recent work has provided evidence that SRY binds directly to a testis-specific enhancer of Sox9
(TES) and activates Sox9 expression in co-operation with steroidogenic factor 1 (SF1).
Furthermore, this SRY action is limited to a certain time period during embryogenesis. The ability
of SRY to initiate testis determination occurs in a narrow time window. Furthermore, SRY also
directly or indirectly inhibits -catenin activity to ensure that the ovary pathway becomes dormant.
This inhibition may involve degradation of the -catenin protein, where SRY or Sox9 directly binds
to –catenin. The Sex-determining Region Y is a gene found on Y chromosomes that leads to the
development of male phenotypes, such as testis. The SRY gene, located on the short branch of the
Y chromosome, initiates male embryonic development in the XY sex determination system. The
SRY gene follows the central dogma of molecular biology; the DNA encoding the gene is
transcribed into messenger RNA, which then produces a single Sry protein. The SRY protein is
also called the testis-determining factor (TDF), a protein that initiates male development in
humans, placental mammals, and marsupials. The Sry protein is a transcription factor that can bind
to regions of testis-specific DNA, bending specific DNA and activating or enhancing its abilities
to promote testis formation, marking the first step towards male, rather than female, development
in the embryo.
3. Researchers have linked mutations in the SRY gene to forms of sex reversal. One example is
Swyers syndrome, a condition in which a person who has XY sex chromosomes develops the
physical characteristics of a female. Mutations in the SRY gene account for between fifteen to
twenty percent of cases of Swyers syndrome. Additionally, the presence of SRY gene in
genetically XX individuals results in XX male syndrome. This state often results from improper
crossing over between X and Y chromosomes during meiosis in the father, resulting in the presence
of SRY gene sequences in X chromosomes. There is also the Parkinson’s disease (PD) which is
debilitating neurodegenerative disorder, triggered by the death of dopamine neurons in the brain
region known as the substantia nigra. Whilst the mechanisms underlying dopamine cell loss in PD,
it is clear that males are more susceptible to PD than females. It has identified that the Y-
chromosome gene, SRY, directs a novel genetic mechanism of dopamine cell death in males
(Czech et al., 2014). Understanding when and how SRY increases the vulnerability of male
dopamine neurons to injury will help explain why males are more susceptible to the PD and to
identify SRY as a novel target for neuroprotective therapy in male PD patients.
4. REFERENCES
Capel B, Swain A, Nicolis S, Hacker A, Walter M, Koopman P, et al. Circular transcripts of the
testis-determining gene Sry in adult mouse testis. Cell 1993; 73:1019–30
McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M. A regulatory cascade hypothesis for
mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl
Acad Sci USA 1993; 90:3368–72.
Ohe K, Lalli E, Sassone-Corsi P. A direct role of SRY and Sox9 proteins in pre-mRNA splicing.
Proc Nat Acad Sci USA 2002; 99:1146–51
Pontiggia A, Rimini R, Harley VR, Goodfellow PN, Lovell-Badge R, Bianchi ME. Sexreversing
mutations affect the architecture of SRY-DNA complexes. EMBO J 1994; 13:6115–24.
Ross DGF, Bowles J, Koopman P, Lehnert S. New insights into SRY regulation through
identification of 5’ conserved sequences. BMC Mol Biol 2008; 9:85.
