Disease relevance of Sox9

• Hypoxia induces chondrocyte-specific gene expression in mesenchymal cells in association with transcriptional activation of Sox9 [1].
• L-Sox5, Sox6, and Sox9 were coexpressed in all precartilaginous condensations in mouse embryos and continued to be expressed in chondrocytes until the cells underwent final hypertrophy [2].
• The down-regulation of Sox9 may have a crucial role in inhibiting expression of the cartilage phenotype in inflammatory joint diseases [3].
• In vivo, either overexpression of Sox9 or inactivation of beta-catenin in chondrocytes of mouse embryos produces a similar phenotype of dwarfism with decreased chondrocyte proliferation, delayed hypertrophic chondrocyte differentiation, and endochondral bone formation [4].
• The Sox9(+/-) mice died perinatally with cleft palate, as well as hypoplasia and bending of many skeletal structures derived from cartilage precursors [5].

High impact information on Sox9

• Here, we show that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry [6].
• Sox9 induces testis development in XX transgenic mice [6].
• To analyze Sox9 function during sex determination, we ectopically expressed this gene in XX gonads [6].
• During embryogenesis, wild-type XX fetal gonads downregulate Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulate and maintain its expression [7].
• Sox9 binds to essential sequences in the Col2a1 and collagen alpha2(XI) gene (Col11a2) chondrocyte-specific enhancers and can activate these enhancers in non-chondrocytic cells [8].

Chemical compound and disease context of Sox9

• Thyroxine downregulates Sox9 and promotes chondrocyte hypertrophy [9].

Biological context of Sox9

• Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis [10].
• A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene [11].
• However, Sox9 expression is detected not only in chondrogenic tissue but also in nonchondrogenic tissues, suggesting the existence of a molecular partner(s) required for Sox9 to control chondrogenesis and chondrogenic gene expression [12].
• We propose that Ods sex reversal is due to the Dct promoter element interacting with gonad-specific enhancer elements to produce the observed male pattern expression of Sox9 in the embryonic gonads [13].
• These phenotypes associated also with the decreased expression of Sox9, Desert hedgehog, Hsd3beta, Platelet/endothelial cell adhesion molecule, and alpha-smooth muscle actin, which are markers of the Sertoli, Leydig, endothelial, and peritubular myoid cells of the developing testis [14].

Anatomical context of Sox9

• We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway [10].
• The Sox9 transcription factor determines glial fate choice in the developing spinal cord [15].
• In agreement, compound loss of Sox9 and Sox10 led to a further decrease in oligodendrocyte progenitors [15].
• Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression [10].
• Astrocyte numbers were also severely reduced in the absence of Sox9 and did not recover at later stages of spinal cord development [15].

Associations of Sox9 with chemical compounds

• A role for the transcription factor NFkappaB in Sox9 down-regulation was suggested by the ability of pyrrolidine dithiocarbamate, an inhibitor of the NFkappaB pathway, to block the effects of IL-1 and TNF-alpha [3].
• Our data indicate a mechanism whereby Sry uses both a cell-autonomous mechanism and a PGD2-mediated signaling mechanism to stimulate expression of Sox9 and induce the differentiation of Sertoli cells in vivo [16].
• We therefore investigated the effects of a synthetic glucocorticoid, dexamethasone (DEX), on Sox9 gene expression in chondrocytes prepared from rib cartilage of newborn mice [17].
• This increased enhancer activity did not occur with a Sox9 mutant harboring serine-to-alanine substitutions in its two consensus protein kinase A phosphorylation sites [18].
• Among these, retinoic acid (RA) specifically enhanced Sox9 mRNA expression in TC6 cells [19].

Physical interactions of Sox9

• Beta-catenin physically interacts through its Armadillo repeats with the C-terminal transactivation domain of Sox9 [4].
• Here, we show that NF-kappaB also suppresses chondrogenesis and destabilizes Sox9 mRNA levels [20].
• Electrophoretic mobility shift assays showed that CRYBP1 bound a specific sequence within the Col2a1 enhancer and inhibited the binding of Sox9, an activator for Col2a1, to the enhancer [21].
• We show here that Sox9 protein is able to bind to a SOX consensus sequence in the CD-RAP promoter [22].
• Highly conserved proximal promoter element harbouring paired Sox9-binding sites contributes to the tissue- and developmental stage-specific activity of the matrilin-1 gene [23].

Co-localisations of Sox9

• Expression of Col2a1 colocalized with expression of Sox9 in all chondroprogenitor cells [24].

Regulatory relationships of Sox9

• These data indicate that activation of SOX9 in the gonad is sufficient to trigger all the downstream events needed for the development of a fully fertile male and provide evidence that Sox9 may down-regulate Wnt4 expression in the gonad [25].
• Here, we show that during oligodendrocyte development, Sox8 is expressed after Sox9, but before Sox10 [26].
• We demonstrate that in Ods, the Dct promoter is capable of acting over a distance of 1 Mb to induce inappropriate expression of Sox9 in the retinal pigmented epithelium of the eye, causing the observed microphthalmia [13].
• No clear indication of Sry-induced enhancement of Sox9 expression was obtained in the present series of experiments [27].
• Hypoxia increased nuclear accumulation of HIF-1alpha and activated the Sox9 promoter [1].

Other interactions of Sox9

• Embryos, in which Sox9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in Sox5; Sox6 double-null mutant mice [10].
• Loss of Sox8 did not impair oligodendrocyte specification by itself, but enhanced the Sox9-dependent defect [26].
• Sox9, the human homolog of which is responsible for the skeletal malformation syndrome campomelic dysplasia, was mapped proximal to D11Mit128 [28].
• Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry [25].
• Long-range activation of Sox9 in Odd Sex (Ods) mice [13].

Analytical, diagnostic and therapeutic context of Sox9

• Sox9 expression levels were measured by quantitative reverse transcriptase-polymerase chain reaction and Northern analysis [29].
• Real-time PCR on these RNA samples, and separate samples from C3H10T1/2 cells, revealed hypoxia-induced changes in the expression of additional genes known to be expressed by chondrocytes including Sox9 and its downstream targets aggrecan and Col2a [1].
• The expression pattern and chromosomal location of Sox9 suggest that it may be the gene defective in the mouse skeletal mutant Tail-short, a potential animal model for campomelic dysplasia [30].
• Down-regulation during myogenic differentiation was also detected in cell culture systems and occurred in parallel with down-regulation of the related Sox9 [31].
• During cartilage expansion, the colocalization of L-Sox5, Sox6, and Sox9 by immunohistochemistry and type II collagen transcripts by in situ hybridization confirmed a close relationship of these transcription factors with the chondrocyte phenotype and cartilage production [32].

References