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General Comment |
Morais da Silva et al. (1996) found that, consistent with its role in sex determination, SOX9 expression closely follows differentiation of Sertoli cells in the mouse testis, in experimental sex reversal when fetal ovaries are grafted to adult kidneys, and in the chick where there is no evidence for an Sry gene. The results suggested to the authors that SOX9 plays an essential role in sex determination, possibly immediately downstream of SRY in mammals, and that it functions as a critical Sertoli cell differentiation factor, perhaps in all vertebrates
NCBI Summary:
The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal.
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Comment |
A MicroRNA (mmu-miR-124) Prevents Sox9 Expression in Developing Mouse Ovarian Cells. Real FM 2013 et al.
In mammals, sex differentiation depends on gonad development, which is controlled by two groups of sex-determining genes that promote one gonadal sex and antagonize the opposite one. SOX9 plays a key role during testis development in all studied vertebrates, whereas it is kept inactive in the XX gonad at the critical time of sex determination, otherwise, ovary-to-testis gonadal sex reversal occurs. However, molecular mechanisms underlying repression of Sox9 at the beginning of ovarian development, as well as other important aspects of gonad organogenesis, largely remain unknown. Since there is indirect evidence that micro-RNAs (miRNA) are necessary for testicular function, the possible involvement of miRNAs in mammalian sex determination deserved further research. Using microarray technology, we have identified 22 miRNAs showing sex-specific expression in the developing gonads during the critical period of sex determination. Bioinformatics analyses led to the identification of miR-124 as a candidate gene for ovarian development. We knocked down or over-expressed miR-124 in primary gonadal cell cultures and observed that miR-124 is sufficient to induce the repression of both SOX9 translation and transcription in ovarian cells. Our results provide the first evidence of the involvement of a miRNA in the regulation of a gene controlling gonad development and sex determination. The miRNA microarray data reported here will help promote further research in this field, to unravel the role of other miRNAs in the genetic control of mammalian sex determination.
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Comment |
Ovarian Germline Stem Cells in the Teleost Fish, Medaka (Oryzias latipes). Nakamura S et al. In the mammalian testis germline stem cells keep producing many sperms, while there is no direct evidence for the presence of germline stem cells in the ovary. It is widely accepted in mammals that the mature oocytes are supplied from a pool of primordial follicles in the adult ovary. In other vertebrates, such as fish, however, there has been no investigation on the mechanism underlying the high egg-producing ability. In this review, we introduce the recently identified ovarian germline stem cells and the surrounding unique structure in teleost fish, medaka (Oryzias latipes) [Nakamura S et al. Science. 2010; 328: 1561-1563]. We also discuss about the expression and function of sox9 that characterizes this unique structure.
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Comment |
Transient expression of SOX9 protein during follicular development in the adult mouse ovary. Notarnicola C et al. SOX9 is an essential activating transcription factor that plays a critical role in Sertoli cell differentiation and subsequent testis cord formation. Cytoplasmic SOX9 is present in both sexes during early gonadal embryogenesis. While in males the protein is later translocated into the nucleus of pre-Sertoli cells, its expression is rapidly turned off in females. In mammalian male gonads, SOX9 activates the expression of anti-M?an hormone (AMH), a male hormone that initiates M?an ducts regression and that is also expressed in postnatal ovarian follicles. Here, we confirm that the SOX9 protein is not present in the immature ovary but also show that SOX9 is transiently expressed in the mature ovary depending on the follicular cycle. Indeed, SOX9 protein was found in the nuclear compartment of the inner cells of the theca interna cell layer which surrounds the pre-antral/antral follicles. In contrast, no expression was detected in the AMH expressing granulosa cells. While these findings exclude the possibility that SOX9 regulates AMH expression in the ovary, they show that SOX9 could nevertheless play a role in the developing follicle.
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Mutations |
3 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Campomelic Dysplasia with or without Sex Reversal
In 6 of 9 patients with campomelic dysplasia (114290), Foster et al. (1994) identified mutations in single alleles of the SOX9 gene. The 3 mutations described in detail would be expected to destroy gene function; 2 caused frameshifts that led to premature chain termination and loss of one-third of the protein (608160.0002, 608160.0003), and 1 caused a premature termination that truncated the protein at 40% of its predicted length (608160.0001). Both parents of 2 of the patients did not have the mutation. The de novo appearance of a mutation in a sex-reversed campomelic patient established that alterations in SOX9 caused both abnormalities. The findings indicated that SOX9 is involved in both bone formation and control of testis development. Foster et al. (1994) suggested that campomelic dysplasia is an autosomal dominant disorder, as they did not detect mutations in both SOX9 alleles of any patient. Dominance appeared to be due to haploinsufficiency rather than gain of function.
Wagner et al. (1994) likewise identified inactivating mutations in 1 SOX9 allele in nontranslocation CMPD-SOX9 cases pointing to haploinsufficiency for SOX9 as the cause of both campomelic dysplasia and autosomal XY sex reversal (see 608160.0005). The 17q breakpoints in 3 translocation cases mapped 50 kb or more from SOX9.
Kwok et al. (1995) analyzed the SOX9 gene in 9 patients with campomelic dysplasia, 2 of whom had chromosome 17 rearrangements, and identified heterozygosity for 2 missense mutations, 3 frameshift mutations, and a splice site mutation, respectively, in 6 of the patients with no cytologically detectable chromosomal aberrations. An identical frameshift mutation (608160.0013) was found in 2 unrelated 46,XY patients, 1 exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). Kwok et al. (1995) noted that these results were consistent with the hypothesis that CMPD results from haploinsufficiency of SOX9.
Sock et al. (2003) presented 2 CMPD patients with de novo mutations in a conserved region preceding the HMG domain of SOX9. A long-term survivor with the acampomelic form of CMPD had an ala76-to-glu amino acid substitution (608160.0009), while a severely affected CMPD patient had an in-frame deletion of amino acid residues 66 through 75 (608160.0010). The conserved domain functions in the related transcription factor SOX10 as a DNA-dependent dimerization domain. The authors demonstrated that like SOX10, SOX9 binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes COL11A2 (120290) and cartilage-derived retinoic acid-sensitive protein (MIA/CDRAP; 601340). Dimerization and the resulting capacity to activate promoters via dimeric binding sites was lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. The authors concluded that the dimerization domain is a third domain essential for SOX9 function during chondrogenesis.
Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: XY Sox9 embryonic loss-of-function mouse mutants show complete sex reversal and produce partially fertile XY oocytes. Lavery R et al. Gonadal differentiation is the first step of mammalian sex determination. The expression of the Y chromosomal testis determining factor Sry leads to up-regulation of the transcription factor Sox9 which promotes testis differentiation. Previous studies showed that Sox9 deficiency induces expression of ovarian markers in XY mutant fetal gonads before they die. To better understand the genome-wide transcriptional profile underlying this process we compared samples from XY Sf1:Cre(Tg/+); Sox9(flox/flox) mutant gonads in which Sox9 is ablated in Sertoli-precursor cells during early stages of gonad development to XX Sox9(flox/flox) ovaries and XY Sox9(flox/flox) testes at E13.5. We found a complex mRNA signature that indicates wide-spread transcriptional de-regulation and revealed for XY mutants at E13.5 an intermediate transcript profile between male and female gonads. However, XY Sf1:Cre(Tg/+); Sox9(flox/flox) mutant gonads develop as ovaries containing XY developing follicles at P0 but less frequently so than in XX control ovaries. Furthermore, we studied the extent to which developing XY mutant ovaries are able to mediate adult fertility and observed that XY oocytes from XY mutant ovaries are competent for fertilization; however, two thirds of them fail to develop beyond two-cell stage embryos. Taken together, we found that XY Sf1:Cre(Tg/+); Sox9(flox/flox) females are capable of producing viable offspring albeit at a reduced level.
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. Benko S et al. BackgroundThe early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.ResultsThrough copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter.ConclusionsThese data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.
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