SRY (Sex Determining Region Y) is a unique gene on the short arm of the Y chromosome involved exclusively in male sex determination and spermatogenesis.
It encodes an inducer of testis formation, the TDF (Testis Determining Factor).
During early embryonic development, the primordial gonads are undifferentiated: they can develop either into ovaries or into testes. In the presence of TDF, the gonads develop into testes, while, in the absence of TDF, they develop into ovaries.
Undifferentiated gonads have two structures: Müllerian system (precursor of female internal sex organs) and Wolffian system (precursor of male internal sex organs):
Sexual differentiation in mammals requires a precise choreography of molecular and cellular events.
Male gonadal differentiation occurs due to the presence of the TDF in males which triggers the differentiation of supporting cell lineage of the undifferentiated gonads into Sertoli cells. Almost all Sertoli cells precursors bear a Y chromosome, this suggests that these cells are the site of Sry expression.
SRY protein has been found in the nuclei of Sertoli cells, in accordance with its role as a transcription factor.
The SRY protein
Sequence analysis of SRY revealed a central region encoding a 79-amino acid motif that is known as “HMG box”, due to its presence in some of the high-mobility-group class of non-histone proteins that associate with DNA.
This observation placed SRY protein among a set of sequence-specific DNA binding transcription factors.
A model of the structure of SRY HMG box bound to DNA
The SRY protein (TDF) binds to a specific nucleotide sequence (5’-CCATTGTTCT) by insertion of an isoleucine (codon AT (ACT) ) in the minor groove of the DNA double helix: this causes the bending of DNA, bringing otherwise distinct regions of the genome into juxtaposition. This bending establishes a particular DNA architecture in chromatin.
In human, SRY mutation of this isoleucine is associated with sex reversal.
SRY interacting proteins
Control of the nuclear localization of specific proteins by NLSs (Nuclear Localization Signals) is an important mechanism for regulating many signal transduction pathways.
- N-terminal NLS forms part of a calmoduline (CaM)-binding domain: this suggests that nuclear import by this NLS is mediated by CaM.
- C-terminal NLS interacts with importin β and has been demonstrated that SRY mutations in the C-terminal NLS result in reduced nuclear import due to reduced binding to importin β.
MIF, testosterone and sex differentiation
Mullerian Inhibiting Factor (MIF)/Anti Mullerian Hormone
Some studies have proposed the MIF gene as a potential target of SRY protein.
The MIF gene, located on chromosome 19p, encodes the MIF which is responsible for the regression of the Müllerian ducts in male fetuses. In fact sex differentiation requires not only testes formation, but also the regression of the precursors of female internal sex organs (Mullerian ducts).
MIF is highly expressed in Sertoli cells.
Other important tasks of Sertoli cells are:
- Induction of primordial germ cells to produce sperm
- Differentiation of primordial gonadal somatic cells into Leydig cells.
Leydig cells produce testosterone which induces masculinization of the external genitalia, differentiation of the Wolffian duct and, subsequently, normal male development.
Other genes involved in sex differentiation
. Sox9 is upregulated in Sertoli cell precursors just after SRY expression begins. SRY is expressed exclusively in these precursor cells, once SOX9 has reached a critical threshold, SRY is repressed by means of a SOX9-dependent negative feedback loop. SOX9 expression is subsequently maintained at high levels in Sertoli cells.
In the absence of Sry or Sox9, supporting cell lineages of the undifferentiated gonads develop in follicular cells and theca cells.
Sox9 has been found to be activated in all cases of XX male sex reversal.
(Steroidogenic factor I ). It plays a role during later testes development and controls androgen synthesis pathways in Leydig cells and MIF activation in Sertoli cells. Sf1-/- embryos don’t develop gonads.
(Desert hedgehog). Is involved in signaling between Sertoli cells and germinal cells.
. Is necessary for spermatogenesis regulation.
Neither Dhh, nor Bmp8 are necessary for testes development.