Disease relevance of SOX10

• Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome [1].
• Ectopic SOX10 expression, in cooperation with cAMP signaling, activated the M-MITF promoter function and the expression of measurable endogenous M-MITF transcripts in neuroblastoma cells [2].
• The SOX10 mutations chosen were E189X, Q377X, and 482ins6, which are associated with WS4, and S135T that is associated with Yemenite deaf-blind hypopigmentation syndrome (YDBS), which does not manifest megacolon [3].
• Four types of WS have been classified to date; in WS type IV (WS4), patients additionally have colonic aganglionosis (Hirschsprung disease, HSCR) [4].
• A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies [5].

Psychiatry related information on SOX10

• Expression of the SOX10 gene during human development [6].
• DOM stimulus generalization was not observed for S(+)-MDA, the N-monomethyl and alpha-demethyl derivatives of MDA, nor for a metabolite of MDA (i.e., 3-methoxy-4-hydroxyphenylisopropylamine) [7].
• DOM significantly increased locomotor activity in an open-field situation at 0.5-1.0 mg/kg i.p., but at doses above 5 mg/kg i.p. caused biphasic changes, i.e. an initial decrease followed by an increase in motility and exploratory behavior [8].

High impact information on SOX10

• Here we report that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway [9].
• The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects [10].
• Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages [10].
• Sox9, by contrast, alters the potential of stem cells from neurogenic to gliogenic, whereas Sox10 is essential for terminal oligodendrocyte differentiation [11].
• Pax3 functions with Sox10 to activate transcription of c-RET, and SOX10 mutations result in Waardenburg-Hirschsprung syndrome [12].

Chemical compound and disease context of SOX10

• Stimulus generalization studies were conducted using rats trained to discriminate 1.0 mg/kg of the phenalkylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline in a two-lever operant procedure [13].
• Tests of stimulus generalization were also conducted with prototypical phenylisopropylamines: (+)amphetamine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) [14].
• However, DOM reduced cyclic AMP level, diminishing the feedback control of cyclic AMP on Ca2+ influx via Ca2+ channels, thereby, allowing continuing enhanced Ca2+ influx, resulting in Ca2+ overload which adversely affects many intracellular processes to induce toxicity [15].

Biological context of SOX10

• These observations explain the phenotype in the mild form of Yemenite deaf-blind syndrome caused by specific SOX10 mutations in the HMG box that abrogate DNA binding without disrupting association with Pax3 [16].
• Analyses revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors [1].
• Here we show that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays [1].
• We show that, like SOX10, SOX9 also binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes Col11a2 and CD-Rap [17].
• M-MITF promoter responsiveness to cAMP was found to depend upon SOX10, and reciprocally, SOX10 transactivation was dependent upon the CRE [2].

Anatomical context of SOX10

• Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness [18].
• The observation that some WS4 patients present with myelination defects of the central and peripheral nervous systems correlates with the recent finding that P(0), a major component of the peripheral myelin, is another transcriptional target of SOX10 [18].
• Other neural crest-related disorders are associated with enteric ganglia defects, such as those caused by mutations in the SOX10 or c-RET genes [16].
• The expression of EDNRB became detectable in HeLa cells after treatment with a demethylating reagent, 5'-aza-2'-deoxycytidine, which was further enhanced in the transformed cells over-expressing SOX10 [19].
• Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10 [18].

Associations of SOX10 with chemical compounds

• Mutational inactivation of this nuclear export signal or treatment of cells with the CRM1-specific export inhibitor leptomycin B inhibited nuclear export and consequently nucleocytoplasmic shuttling of Sox10 [20].
• Rats trained to discriminate (+/-) 2,5-dimethoxy-4-methylphenylisopropylamine (DOM) (1.0 mg/kg) from saline, using a standard two-lever operant task, were challenged with various doses of 3,4-methylenedioxyphenylisopropylamine (MDA) and several related agents [7].
• The biological data are contrasted with the corresponding results obtained with the potent human psychotogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) [21].
• The effects of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-ethylamphetamine (DOET), d-amphetamine, and cocaine in rats trained with mescaline as a discriminative stimulus [22].
• Similar effects were produced by indoleamine hallucinogens, such as LSD, N,N-dimethyltryptamine, and psilocin, and by phenylethylamine hallucinogens, such as mescaline or 2,5-dimethoxy-4-methylamphetamine (DOM) [23].

Physical interactions of SOX10

• Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter [24].
• Finally, we present data suggesting that recombinant Sox10 protein can directly interact with a previously characterized regulatory region of the beta4 gene [25].

Regulatory relationships of SOX10

• Here, we provide evidence that SOX10 regulates the expression of EDNRB gene in human melanocyte-lineage cells, as judged by RNA interference and chromatin immunoprecipitation analyses [19].
• A tissue-restricted cAMP transcriptional response: SOX10 modulates alpha-melanocyte-stimulating hormone-triggered expression of microphthalmia-associated transcription factor in melanocytes [2].
• Moreover, a transcription factor Sp1 enhances the degree of the SOX10-mediated transactivation of the EDNRB promoter through these cis-acting elements [19].
• Consistent with such a role, the proportion of Sox10-expressing progenitors in the total population of enteric neural crest cells is reduced in the gut of endothelin 3-deficient embryos [26].
• Investigation of Sox10 in PA revealed that it is highly overexpressed relative to other pediatric brain tumors, lending support to the theory that Sox10-regulated overexpression of ErbB3 may be driving growth in PA [27].

Other interactions of SOX10

• In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects fail to transactivate the Cx32 promoter [18].
• SOX10 transactivates the EDNRB promoter through the cis-acting elements, the two CA-rich sequences and the GC box [19].
• In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelin defects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10 [18].
• Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10 [18].
• Of these, the POU domain factor BRN2 and the SOX family member SOX10 are both highly expressed in unpigmented melanocyte precursors but are down-regulated upon differentiation [28].

Analytical, diagnostic and therapeutic context of SOX10

• In situ hybridization experiments carried out in the dominant megacolon (DOM:) mouse, confirmed that SOX10 dysfunction impairs MITF: expression as well as melanocytic development and survival [1].
• We here describe a novel mutant mouse with a mutation of the Ednrb gene, and propose the mouse as an animal model of WS4 [29].
• We applied immunohistochemistry to analyze whether the expression of SOX10 can differentiate astrocytoma and oligodendroglioma [30].
• The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy [31].
• Using a clonal cell culture system, we show that SOX10 inhibits overt neuronal and glial differentiation of multilineage ENS progenitor cells (EPCs), without interfering with their neurogenic commitment [26].

References