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Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells.
Dravis C, Spike BT, Harrell JC, Johns C, Trejo CL, Southard-Smith EM, Perou CM, Wahl GM
(2015) Cell Rep 12: 2035-48
MeSH Terms: Animals, Breast Neoplasms, Cell Culture Techniques, Cell Differentiation, Epithelial Cells, Epithelial-Mesenchymal Transition, Female, Fetus, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, Gene Expression Regulation, Neoplastic, Humans, Mammary Glands, Animal, Mammary Glands, Human, Mesenchymal Stem Cells, Mice, SOXE Transcription Factors, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured
Show Abstract · Added September 28, 2015
To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor Sox10. Here, we show that Sox10 is specifically expressed in mammary cells exhibiting the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence whereas its overexpression increases stem/progenitor activity. Intriguingly, we also show that Sox10 overexpression causes mammary cells to undergo a mesenchymal transition. Consistent with these findings, Sox10 is preferentially expressed in stem- and mesenchymal-like breast cancers. These results demonstrate a signaling mechanism through which stem and mesenchymal states are acquired in mammary cells and suggest therapeutic avenues in breast cancers for which targeted therapies are currently unavailable.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Granular cell tumors overexpress TFE3 without corollary gene rearrangement--Reply.
Chamberlain BK, McClain CM, Gonzalez RS, Coffin CM, Cates JM
(2015) Hum Pathol 46: 1243
MeSH Terms: Humans, Inhibins, Nestin, S100 Proteins, SOXE Transcription Factors, Sarcoma, Alveolar Soft Part
Added February 15, 2016
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6 MeSH Terms
Alveolar soft part sarcoma and granular cell tumor: an immunohistochemical comparison study.
Chamberlain BK, McClain CM, Gonzalez RS, Coffin CM, Cates JM
(2014) Hum Pathol 45: 1039-44
MeSH Terms: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Calbindin 2, Granular Cell Tumor, Humans, Immunohistochemistry, Inhibins, Nestin, S100 Proteins, SOXE Transcription Factors, Sarcoma, Alveolar Soft Part, Sensitivity and Specificity, Staining and Labeling
Show Abstract · Added February 15, 2016
Although the histologic features of alveolar soft part sarcoma and granular cell tumor are typically distinctive, occasional cases show a significant morphologic overlap. Differentiating these entities is crucial because granular cell tumor is almost always benign and alveolar soft part sarcoma is invariably malignant. We evaluated a panel of immunohistochemical stains (S-100 protein, inhibin, SOX10, nestin, calretinin, and TFE3) in 13 alveolar soft part sarcomas and 11 granular cell tumors. Tissue sections were also stained by the periodic acid-Schiff method after diastase digestion (PAS-D) and evaluated for coarse cytoplasmic granularity or crystalline cytoplasmic inclusions. S-100 protein, inhibin, SOX10, and nestin each distinguished granular cell tumor and alveolar soft part sarcoma with 100% sensitivity and specificity. PAS-D staining also distinguished cases with 100% accuracy, as granular cell tumor consistently demonstrated coarsely granular, PAS-D-positive cytoplasm and alveolar soft part sarcoma showed only focal intracytoplasmic crystalline inclusions. Although all granular cell tumors were calretinin positive, so were 46% of alveolar soft part sarcomas. TFE3 was positive in 91% of granular cell tumors and all alveolar soft part sarcomas. Together with PAS-D, immunohistochemical stains for S-100 protein, inhibin, SOX10, and nestin accurately identify alveolar soft part sarcoma and granular cell tumor. Although TFE3 has been reported as a relatively specific marker for alveolar soft part sarcoma, it should be recalled that it is also expressed in most granular cell tumors.
Copyright © 2014 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas.
Ivanov SV, Panaccione A, Nonaka D, Prasad ML, Boyd KL, Brown B, Guo Y, Sewell A, Yarbrough WG
(2013) Br J Cancer 109: 444-51
MeSH Terms: Adult, Animals, Biomarkers, Tumor, Breast Neoplasms, Carcinoma, Adenoid Cystic, Carcinoma, Basal Cell, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Prognosis, SOXE Transcription Factors, Salivary Gland Neoplasms, Transcriptome
Show Abstract · Added March 20, 2014
BACKGROUND - Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15-20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers.
METHODS - Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation.
RESULTS - In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines.
CONCLUSION - SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools.
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15 MeSH Terms
Isolation and live imaging of enteric progenitors based on Sox10-Histone2BVenus transgene expression.
Corpening JC, Deal KK, Cantrell VA, Skelton SB, Buehler DP, Southard-Smith EM
(2011) Genesis 49: 599-618
MeSH Terms: Alleles, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Enteric Nervous System, Female, Gene Expression Regulation, Developmental, Gene Order, Histones, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Molecular Imaging, Mutation, Neural Crest, Organ Specificity, SOXE Transcription Factors, Stem Cells, Transgenes
Show Abstract · Added December 5, 2013
To facilitate dynamic imaging of neural crest (NC) lineages and discrimination of individual cells in the enteric nervous system (ENS) where close juxtaposition often complicates viewing, we generated a mouse BAC transgenic line that drives a Histone2BVenus (H2BVenus) reporter from Sox10 regulatory regions. This strategy does not alter the endogenous Sox10 locus and thus facilitates analysis of normal NC development. Our Sox10-H2BVenus BAC transgene exhibits temporal, spatial, and cell-type specific expression that reflects endogenous Sox10 patterns. Individual cells exhibiting nuclear-localized fluorescence of the H2BVenus reporter are readily visualized in both fixed and living tissue and are amenable to isolation by fluorescence activated cell sorting (FACS). FACS-isolated H2BVenus+ enteric NC-derived progenitors (ENPs) exhibit multipotency, readily form neurospheres, self-renew in vitro and express a variety of stem cell genes. Dynamic live imaging as H2BVenus+ ENPs migrate down the fetal gut reveals cell fragmentation suggesting that apoptosis occurs at a low frequency during normal development of the ENS. Confocal imaging both during population of the fetal intestine and in postnatal gut muscle strips revealed differential expression between individual cells consistent with down-regulation of the transgene as progression towards non-glial fates occurs. The expression of the Sox10-H2BVenus transgene in multiple regions of the peripheral nervous system will facilitate future studies of NC lineage segregation as this tool is expressed in early NC progenitors and maintained in enteric glia.
Copyright © 2011 Wiley-Liss, Inc.
2 Communities
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22 MeSH Terms
Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease.
Walters LC, Cantrell VA, Weller KP, Mosher JT, Southard-Smith EM
(2010) Hum Mol Genet 19: 4353-72
MeSH Terms: Animals, CD57 Antigens, Disease Models, Animal, Enteric Nervous System, Ganglia, Hirschsprung Disease, Humans, Immunohistochemistry, Intestine, Small, Intestines, Mice, Mice, Congenic, Mice, Inbred C3H, Mice, Inbred C57BL, Mutation, Neural Crest, SOXE Transcription Factors, Species Specificity, Stem Cells
Show Abstract · Added November 14, 2013
Abnormalities in the development of enteric neural crest-derived progenitors (ENPs) that generate the enteric nervous system (ENS) can lead to aganglionosis in a variable portion of the distal gastrointestinal tract. Cumulative evidence suggests that variation of aganglionosis is due to gene interactions that modulate the ability of ENPs to populate the intestine; however, the developmental processes underlying this effect are unknown. We hypothesized that differences in enteric ganglion deficits could be attributable to the effects of genetic background on early developmental processes, including migration, proliferation, or lineage divergence. Developmental processes were investigated in congenic Sox10(Dom) mice, an established Hirschsprung disease (HSCR) model, on distinct inbred backgrounds, C57BL/6J (B6) and C3HeB/FeJ (C3Fe). Immuno-staining on whole-mount fetal gut tissue and dissociated cell suspensions was used to assess migration and proliferation. Flow cytometry utilizing the cell surface markers p75 and HNK-1 was used to isolate live ENPs for analysis of developmental potential. Frequency of ENPs was reduced in Sox10(Dom) embryos relative to wild-type embryos, but was unaffected by genetic background. Both migration and developmental potential of ENPs in Sox10(Dom) embryos were altered by inbred strain background with the most highly significant differences seen for developmental potential between strains and genotypes. In vivo imaging of fetal ENPs and postnatal ganglia demonstrates that altered lineage divergence impacts ganglia in the proximal intestine. Our analysis demonstrates that genetic background alters early ENS development and suggests that abnormalities in lineage diversification can shift the proportions of ENP populations and thus may contribute to ENS deficiencies in vivo.
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19 MeSH Terms
Distant regulatory elements in a Sox10-beta GEO BAC transgene are required for expression of Sox10 in the enteric nervous system and other neural crest-derived tissues.
Deal KK, Cantrell VA, Chandler RL, Saunders TL, Mortlock DP, Southard-Smith EM
(2006) Dev Dyn 235: 1413-32
MeSH Terms: 5' Flanking Region, Animals, Cell Line, Tumor, Chromosomes, Artificial, Bacterial, Enteric Nervous System, Female, High Mobility Group Proteins, Male, Melanoma, Experimental, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Neural Crest, Rats, Regulatory Sequences, Nucleic Acid, SOXE Transcription Factors, Transcription Factors, Transgenes
Show Abstract · Added August 13, 2010
Sox10 is an essential transcription factor required for development of neural crest-derived melanocytes, peripheral glia, and enteric ganglia. Multiple transcriptional targets regulated by Sox10 have been identified; however, little is known regarding regulation of Sox10. High sequence conservation surrounding 5' exons 1 through 3 suggests these regions might contain functional regulatory elements. However, we observed that these Sox10 genomic sequences do not confer appropriate cell-specific transcription in vitro when linked to a heterologous reporter. To identify elements required for expression of Sox10 in vivo, we modified bacterial artificial chromosomes (BACs) to generate a Sox10betaGeoBAC transgene. Our approach leaves endogenous Sox10 loci unaltered, circumventing haploinsufficiency issues that arise from gene targeting. Sox10betaGeoBAC expression closely approximates Sox10 expression in vivo, resulting in expression in anterior dorsal neural tube at embryonic day (E) 8.5 and in cranial ganglia, otic vesicle, and developing dorsal root ganglia at E10.5. Characterization of Sox10betaGeoBAC expression confirms the presence of essential regulatory regions and additionally identifies previously unreported expression in thyroid parafollicular cells, thymus, salivary, adrenal, and lacrimal glands. Fortuitous deletions in independent Sox10betaGeoBAC lines result in loss of transgene expression in peripheral nervous system lineages and coincide with evolutionarily conserved regions. Our analysis indicates that Sox10 expression requires the presence of distant cis-acting regulatory elements. The Sox10betaGeoBAC transgene offers one avenue for specifically testing the role of individual conserved regions in regulation of Sox10 and makes possible analysis of Sox10+ derivatives in the context of normal neural crest development.
(c) 2006 Wiley-Liss, Inc.
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19 MeSH Terms
Genetic evidence does not support direct regulation of EDNRB by SOX10 in migratory neural crest and the melanocyte lineage.
Hakami RM, Hou L, Baxter LL, Loftus SK, Southard-Smith EM, Incao A, Cheng J, Pavan WJ
(2006) Mech Dev 123: 124-34
MeSH Terms: Animals, Cell Lineage, Gene Expression Regulation, Developmental, Heterozygote, High Mobility Group Proteins, Hypopigmentation, Intramolecular Oxidoreductases, Melanocytes, Mice, Mice, Mutant Strains, Mutation, Neoplasm Proteins, Neural Crest, Promoter Regions, Genetic, Receptor, Endothelin B, SOXE Transcription Factors, Transcription Factors
Show Abstract · Added May 19, 2014
Mutations in the transcription factor Sox10 or Endothelin Receptor B (Ednrb) result in Waardenburg Syndrome Type IV (WS-IV), which presents with deficiencies of neural crest derived melanocytes (hypopigmentation) and enteric ganglia (hypoganglionosis). As Sox10 and Ednrb are expressed in mouse migratory neural crest cells and melanoblasts, we investigated the possibility that SOX10 and EDNRB function through a hierarchical relationship during melanocyte development. However, our results support a distinct rather than hierarchical relationship. First, SOX10 expression continues in Ednrb null melanoblasts, demonstrating that SOX10 expression is not dependent on EDNRB function. Second, Ednrb expression persists in E10.5 Sox10null embryos, demonstrating that Ednrb is not dependent on SOX10 for expression in migratory neural crest cells. Third, over-expression of SOX10 in melanoblasts of mice that harbor null or hypomorphic Ednrb alleles does not rescue hypopigmentation, suggesting that SOX10 overexpression can neither complement a lack of EDNRB function nor increase Ednrb expression. Fourth, mice that are double heterozygous for loss-of-function mutations in Sox10 and Ednrb do not demonstrate synergistically increased hypopigmentation compared to mice that are single heterozygotes for either mutation alone, suggesting a lack of direct genetic interaction between these genes. Our results suggest that SOX10 does not directly activate Ednrb transcription in the melanocyte lineage. Given that SOX10 directly activates Ednrb in the enteric nervous system, our results suggest that SOX10 may differentially activate target genes based on the particular cellular context.
1 Communities
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17 MeSH Terms
Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10Dom model of Hirschsprung disease.
Owens SE, Broman KW, Wiltshire T, Elmore JB, Bradley KM, Smith JR, Southard-Smith EM
(2005) Hum Mol Genet 14: 1549-58
MeSH Terms: Alleles, Animals, Chromosomes, Human, Pair 5, DNA-Binding Proteins, Genetic Linkage, Genome, Human, High Mobility Group Proteins, Hirschsprung Disease, Humans, Mice, Models, Genetic, Quantitative Trait Loci, SOXE Transcription Factors, Transcription Factors
Show Abstract · Added March 20, 2014
Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain-dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with aganglionosis. In this study, we focused on enteric ganglia deficits in Sox10Dom mice and defined aganglionosis as a quantitative trait in Sox10Dom intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10Dom/+ mutants ranges over a continuum from severe aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent aganglionosis, we performed a single nucleotide polymorphism-based genome scan in Sox10Dom/+ F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of aganglionosis. Three of these loci on chromosomes 3, 8 and 11 do not coincide with previously known aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.
1 Communities
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14 MeSH Terms
Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10Dom mouse model of Hirschsprung disease.
Cantrell VA, Owens SE, Chandler RL, Airey DC, Bradley KM, Smith JR, Southard-Smith EM
(2004) Hum Mol Genet 13: 2289-301
MeSH Terms: Animals, Crosses, Genetic, DNA-Binding Proteins, Endothelins, Enteric Nervous System, Genes, Dominant, High Mobility Group Proteins, Hirschsprung Disease, Mice, Mice, Congenic, Mice, Inbred C3H, Mice, Inbred C57BL, Mutation, Pedigree, Receptor, Endothelin B, SOXE Transcription Factors, Severity of Illness Index, Signal Transduction, Transcription Factors
Show Abstract · Added March 20, 2014
Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest (NC) cells to populate the developing gut. One of the essential genes for this process is the NC transcription factor Sox10. Sox10Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric aganglionosis that are analogous to the variable aganglionosis seen in human HSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine whether known HSCR susceptibility loci are acting as modifiers of Sox10, we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and Sox10 mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system in mouse models and suggests that this interaction could contribute to the epistatic network producing variation between patients with aganglionosis.
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19 MeSH Terms