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Michael Wegner - One of the best experts on this subject based on the ideXlab platform.
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Sox13 functionally complements the related Sox5 and Sox6 as important developmental modulators in mouse spinal cord oligodendrocytes.
Journal of neurochemistry, 2015Co-Authors: Tina Baroti, Anja Schillinger, Michael Wegner, Claus C StoltAbstract:The role of transcription factor Sox13, which together with Sox5 and Sox6 belongs to the SoxD family, is only poorly characterized in central nervous system development. Therefore, we analysed whether Sox13 expression and function overlaps with or differs from that of its close relatives Sox5 and Sox6. In the developing mouse spinal cord, we found Sox13 predominantly expressed in neuroepithelial precursors, oligodendroglial and astroglial cells. The substantially overlapping expression with Sox5 and Sox6 in oligodendroglial cells prompted us to study potential roles during specification, lineage progression and differentiation of oligodendrocytes. In contrast to Sox5 and Sox6, Sox13 expression continues after differentiation and even increases in myelinating oligodendrocytes. Sox13 deletion did not interfere with oligodendroglial development, which was normal in Sox13-deficient mice. However, the premature differentiation of oligodendrocyte precursors triggered by loss of Sox6 was slightly more prominent in Sox6/Sox13 double-deficient mice. Sox13 can bind to the same sites in myelin gene promoters as Sox5 and Sox6 in vitro. Reporter gene assays furthermore reveal a similar antagonizing effect on SOX10-dependent transactivation of myelin gene promoters as previously shown for Sox5 and Sox6. This argues that Sox13 is functionally redundant with the other SoxD proteins and complements Sox5 and Sox6 in their role as important modulators of oligodendrocyte development. The transcription factor Sox13 is co-expressed with the related Sox5 and Sox6 in cells of the oligodendroglial lineage. By itself, it has little impact on oligodendrocyte development but supports Sox5 and Sox6 during the process as a functionally redundant transcription factor.
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sox12 deletion in the mouse reveals nonreciprocal redundancy with the related sox4 and sox11 transcription factors
Molecular and Cellular Biology, 2008Co-Authors: Melanie Hoser, Michael R Bösl, Michaela R Potzner, Julia M C Koch, Michael Wegner, Elisabeth SockAbstract:The transcription factors Sox4 and Sox11 are important regulators of diverse developmental processes including heart, lung, pancreas, spleen, and B-cell development. Here we have studied the role of the related Sox12 as the third protein of the SoxC group both in vivo and in vitro. Despite widespread Sox12 expression during embryonic development, Sox12-deficient mice developed surprisingly normally, so that they were born alive, showed no gross phenotypic abnormalities, and were fertile in both sexes. Comparison with the related Sox4 and Sox11 revealed extensive overlap in the embryonic expression pattern but more uniform expression levels for Sox12, without sites of particularly high expression. All three Sox proteins furthermore exhibited comparable DNA-binding characteristics and functioned as transcriptional activators. Sox12 was, however, a relatively weak transactivator in comparison to Sox11. We conclude that Sox4 and Sox11 function redundantly with Sox12 and can compensate its loss during mouse development. Because of differences in expression levels and transactivation rates, however, functional compensation is not reciprocal.
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replacement of the SOX10 transcription factor by sox8 reveals incomplete functional equivalence
Development, 2006Co-Authors: Susanne Kellerer, Michael R Bösl, Claus C Stolt, Silke Schreiner, Stefanie Scholz, Michael WegnerAbstract:Sox8 and SOX10 are two closely related transcription factors of the Sox protein family with overlapping expression patterns during development. They are believed to perform very similar functions because several developmental processes, including enteric nervous system development and oligodendrocyte differentiation, are regulated by both Sox proteins. To analyze the extent of functional equivalence between the two Sox proteins, we employed targeted mutagenesis to replace SOX10 with Sox8 in the mouse. In mice that expressed Sox8 instead of SOX10, SOX10 deficiency was phenotypically rescued to different extents in affected tissues. Whereas development of glial cells and neurons in the sensory and sympathetic parts of the peripheral nervous system was almost normal when SOX10 was replaced by Sox8, melanocyte development was as defective as in SOX10-deficient mice. The ability of Sox8 to rescue the defects in enteric nervous system development and oligodendrocyte differentiation of SOX10-deficient mice was limited. We conclude that the extent of functional equivalence depends on the tissue and that, despite their relatedness, Sox8 and SOX10 have more unique functions than previously appreciated.
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from stem cells to neurons and glia a soxist s view of neural development
Trends in Neurosciences, 2005Co-Authors: Michael Wegner, Claus C StoltAbstract:During nervous system development, neural stem cells give rise to many different types of neurons and glia over an extended period. Little is known about the intrinsic factors that regulate stem-cell maintenance, decide whether neurons or glia are generated, or control terminal differentiation. Transcription factors of the Sox family provide important clues about the control of these events. In the central nervous system (CNS), Sox1, Sox2 and Sox3 are required for stem-cell maintenance, and their effects are counteracted by Sox21. Sox9, by contrast, alters the potential of stem cells from neurogenic to gliogenic, whereas SOX10 is essential for terminal oligodendrocyte differentiation. In the peripheral nervous system (PNS) the same Sox proteins have different functions, uncovering important developmental differences between the CNS and PNS.
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identification of sox8 as a modifier gene in a mouse model of hirschsprung disease reveals underlying molecular defect
Developmental Biology, 2005Co-Authors: Marzena Maka, Claus C Stolt, Michael WegnerAbstract:Mice carrying heterozygous mutations in the SOX10 gene display aganglionosis of the colon and represent a model for human Hirschsprung disease. Here, we show that the closely related Sox8 functions as a modifier gene for SOX10-dependent enteric nervous system defects as it increases both penetrance and severity of the defect in SOX10 heterozygous mice despite having no detectable influence on enteric nervous system development on its own. Sox8 exhibits an expression pattern very similar to SOX10 with occurrence in vagal and enteric neural crest cells and later confinement to enteric glia. Loss of Sox8 alleles in SOX10 heterozygous mice impaired colonization of the gut by enteric neural crest cells already at early times. Whereas proliferation, apoptosis, and neuronal differentiation were normal for enteric neural crest cells in the gut of mutant mice, apoptosis was dramatically increased in vagal neural crest cells outside the gut. The defects in enteric nervous system development of mice with SOX10 and Sox8 mutations are therefore likely caused by a reduction of the pool of undifferentiated vagal neural crest cells. Our study suggests that Sox8 and SOX10 are jointly required for the maintenance of these vagal neural crest stem cells.
Yihleong Chang - One of the best experts on this subject based on the ideXlab platform.
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SOX10 positive salivary gland tumors a growing list including mammary analogue secretory carcinoma of the salivary gland sialoblastoma low grade salivary duct carcinoma basal cell adenoma adenocarcinoma and a subgroup of mucoepidermoid carcinoma
Human Pathology, 2016Co-Authors: Minshu Hsieh, Yihsuan Lee, Yihleong ChangAbstract:Transcription factor SRY-related HMG-box 10 (SOX10) is an important marker for melanocytic, schwannian, myoepithelial, and some salivary gland tumors. The aim of this study was to investigate SOX10 expression more thoroughly in the salivary gland neoplasms, including mammary analogue secretory carcinoma and hyalinizing clear cell carcinoma harboring specific genetic rearrangements. A new rabbit monoclonal anti-SOX10 antibody (clone EP268) was used to examine SOX10 expression in 14 different types of salivary gland tumors. We found that acinic cell carcinoma (AciCC), adenoid cystic carcinoma, mammary analogue secretory carcinoma (MASC), epithelial-myoepithelial carcinoma, low-grade salivary duct carcinoma, sialoblastoma, basal cell adenocarcinoma, basal cell adenoma, and pleomorphic adenoma were SOX10 positive. Salivary duct carcinoma, lymphoepithelial carcinoma, hyalinizing clear cell carcinoma, and oncocytoma were SOX10 negative. Earlier, mucoepidermoid carcinoma (MEC) was considered a SOX10-negative tumor. This study identified a subgroup of SOX10-positive MEC cases with characteristic polygonal epithelial cells, pale-to-eosinophilic cytoplasm, and colloid-like dense eosinophilic material. Our data show SOX10 expression can be observed in salivary gland tumors with either one of the 4 cell types: acinic cells, cuboidal ductal cells with low-grade cytologic features, basaloid cells, and myoepithelial cells. In this article we thoroughly evaluated SOX10 expression in salivary gland tumors. SOX10 is useful in the differential diagnosis between myoepithelial carcinoma with clear cell features and hyalinizing clear cell carcinoma. It can also be used to discriminate low-grade salivary duct carcinoma from high-grade ones. Pathologists should be cautious with the interpretation of SOX10 positivity in salivary gland tumors, and correlation with histologic feature is mandatory.
Claus C Stolt - One of the best experts on this subject based on the ideXlab platform.
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the transcription factor SOX10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland
Scientific Reports, 2020Co-Authors: Svenja Mertelmeyer, Matthias Weider, Claus C Stolt, Tina Baroti, Franziska Frob, Simone Reiprich, Kay Uwe WagnerAbstract:The high mobility group-domain containing transcription factor SOX10 is an essential regulator of developmental processes and homeostasis in the neural crest, several neural crest-derived lineages and myelinating glia. Recent studies have also implicated SOX10 as an important factor in mammary stem and precursor cells. Here we employ a series of mouse mutants with constitutive and conditional SOX10 deficiencies to show that SOX10 has multiple functions in the developing mammary gland. While there is no indication for a requirement of SOX10 in the specification of the mammary placode or descending mammary bud, it is essential for both the prenatal hormone-independent as well as the pubertal hormone-dependent branching of the mammary epithelium and for proper alveologenesis during pregnancy. It furthermore acts in a dosage-dependent manner. SOX10 also plays a role during the involution process at the end of the lactation period. Whereas its effect on epithelial branching and alveologenesis are likely causally related to its function in mammary stem and precursor cells, this is not the case for its function during involution where SOX10 seems to work at least in part through regulation of the miR-424(322)/503 cluster.
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Sox13 functionally complements the related Sox5 and Sox6 as important developmental modulators in mouse spinal cord oligodendrocytes.
Journal of neurochemistry, 2015Co-Authors: Tina Baroti, Anja Schillinger, Michael Wegner, Claus C StoltAbstract:The role of transcription factor Sox13, which together with Sox5 and Sox6 belongs to the SoxD family, is only poorly characterized in central nervous system development. Therefore, we analysed whether Sox13 expression and function overlaps with or differs from that of its close relatives Sox5 and Sox6. In the developing mouse spinal cord, we found Sox13 predominantly expressed in neuroepithelial precursors, oligodendroglial and astroglial cells. The substantially overlapping expression with Sox5 and Sox6 in oligodendroglial cells prompted us to study potential roles during specification, lineage progression and differentiation of oligodendrocytes. In contrast to Sox5 and Sox6, Sox13 expression continues after differentiation and even increases in myelinating oligodendrocytes. Sox13 deletion did not interfere with oligodendroglial development, which was normal in Sox13-deficient mice. However, the premature differentiation of oligodendrocyte precursors triggered by loss of Sox6 was slightly more prominent in Sox6/Sox13 double-deficient mice. Sox13 can bind to the same sites in myelin gene promoters as Sox5 and Sox6 in vitro. Reporter gene assays furthermore reveal a similar antagonizing effect on SOX10-dependent transactivation of myelin gene promoters as previously shown for Sox5 and Sox6. This argues that Sox13 is functionally redundant with the other SoxD proteins and complements Sox5 and Sox6 in their role as important modulators of oligodendrocyte development. The transcription factor Sox13 is co-expressed with the related Sox5 and Sox6 in cells of the oligodendroglial lineage. By itself, it has little impact on oligodendrocyte development but supports Sox5 and Sox6 during the process as a functionally redundant transcription factor.
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replacement of the SOX10 transcription factor by sox8 reveals incomplete functional equivalence
Development, 2006Co-Authors: Susanne Kellerer, Michael R Bösl, Claus C Stolt, Silke Schreiner, Stefanie Scholz, Michael WegnerAbstract:Sox8 and SOX10 are two closely related transcription factors of the Sox protein family with overlapping expression patterns during development. They are believed to perform very similar functions because several developmental processes, including enteric nervous system development and oligodendrocyte differentiation, are regulated by both Sox proteins. To analyze the extent of functional equivalence between the two Sox proteins, we employed targeted mutagenesis to replace SOX10 with Sox8 in the mouse. In mice that expressed Sox8 instead of SOX10, SOX10 deficiency was phenotypically rescued to different extents in affected tissues. Whereas development of glial cells and neurons in the sensory and sympathetic parts of the peripheral nervous system was almost normal when SOX10 was replaced by Sox8, melanocyte development was as defective as in SOX10-deficient mice. The ability of Sox8 to rescue the defects in enteric nervous system development and oligodendrocyte differentiation of SOX10-deficient mice was limited. We conclude that the extent of functional equivalence depends on the tissue and that, despite their relatedness, Sox8 and SOX10 have more unique functions than previously appreciated.
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from stem cells to neurons and glia a soxist s view of neural development
Trends in Neurosciences, 2005Co-Authors: Michael Wegner, Claus C StoltAbstract:During nervous system development, neural stem cells give rise to many different types of neurons and glia over an extended period. Little is known about the intrinsic factors that regulate stem-cell maintenance, decide whether neurons or glia are generated, or control terminal differentiation. Transcription factors of the Sox family provide important clues about the control of these events. In the central nervous system (CNS), Sox1, Sox2 and Sox3 are required for stem-cell maintenance, and their effects are counteracted by Sox21. Sox9, by contrast, alters the potential of stem cells from neurogenic to gliogenic, whereas SOX10 is essential for terminal oligodendrocyte differentiation. In the peripheral nervous system (PNS) the same Sox proteins have different functions, uncovering important developmental differences between the CNS and PNS.
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identification of sox8 as a modifier gene in a mouse model of hirschsprung disease reveals underlying molecular defect
Developmental Biology, 2005Co-Authors: Marzena Maka, Claus C Stolt, Michael WegnerAbstract:Mice carrying heterozygous mutations in the SOX10 gene display aganglionosis of the colon and represent a model for human Hirschsprung disease. Here, we show that the closely related Sox8 functions as a modifier gene for SOX10-dependent enteric nervous system defects as it increases both penetrance and severity of the defect in SOX10 heterozygous mice despite having no detectable influence on enteric nervous system development on its own. Sox8 exhibits an expression pattern very similar to SOX10 with occurrence in vagal and enteric neural crest cells and later confinement to enteric glia. Loss of Sox8 alleles in SOX10 heterozygous mice impaired colonization of the gut by enteric neural crest cells already at early times. Whereas proliferation, apoptosis, and neuronal differentiation were normal for enteric neural crest cells in the gut of mutant mice, apoptosis was dramatically increased in vagal neural crest cells outside the gut. The defects in enteric nervous system development of mice with SOX10 and Sox8 mutations are therefore likely caused by a reduction of the pool of undifferentiated vagal neural crest cells. Our study suggests that Sox8 and SOX10 are jointly required for the maintenance of these vagal neural crest stem cells.
Minshu Hsieh - One of the best experts on this subject based on the ideXlab platform.
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SOX10 positive salivary gland tumors a growing list including mammary analogue secretory carcinoma of the salivary gland sialoblastoma low grade salivary duct carcinoma basal cell adenoma adenocarcinoma and a subgroup of mucoepidermoid carcinoma
Human Pathology, 2016Co-Authors: Minshu Hsieh, Yihsuan Lee, Yihleong ChangAbstract:Transcription factor SRY-related HMG-box 10 (SOX10) is an important marker for melanocytic, schwannian, myoepithelial, and some salivary gland tumors. The aim of this study was to investigate SOX10 expression more thoroughly in the salivary gland neoplasms, including mammary analogue secretory carcinoma and hyalinizing clear cell carcinoma harboring specific genetic rearrangements. A new rabbit monoclonal anti-SOX10 antibody (clone EP268) was used to examine SOX10 expression in 14 different types of salivary gland tumors. We found that acinic cell carcinoma (AciCC), adenoid cystic carcinoma, mammary analogue secretory carcinoma (MASC), epithelial-myoepithelial carcinoma, low-grade salivary duct carcinoma, sialoblastoma, basal cell adenocarcinoma, basal cell adenoma, and pleomorphic adenoma were SOX10 positive. Salivary duct carcinoma, lymphoepithelial carcinoma, hyalinizing clear cell carcinoma, and oncocytoma were SOX10 negative. Earlier, mucoepidermoid carcinoma (MEC) was considered a SOX10-negative tumor. This study identified a subgroup of SOX10-positive MEC cases with characteristic polygonal epithelial cells, pale-to-eosinophilic cytoplasm, and colloid-like dense eosinophilic material. Our data show SOX10 expression can be observed in salivary gland tumors with either one of the 4 cell types: acinic cells, cuboidal ductal cells with low-grade cytologic features, basaloid cells, and myoepithelial cells. In this article we thoroughly evaluated SOX10 expression in salivary gland tumors. SOX10 is useful in the differential diagnosis between myoepithelial carcinoma with clear cell features and hyalinizing clear cell carcinoma. It can also be used to discriminate low-grade salivary duct carcinoma from high-grade ones. Pathologists should be cautious with the interpretation of SOX10 positivity in salivary gland tumors, and correlation with histologic feature is mandatory.
William J Pavan - One of the best experts on this subject based on the ideXlab platform.
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a dual role for SOX10 in the maintenance of the postnatal melanocyte lineage and the differentiation of melanocyte stem cell progenitors
PLOS Genetics, 2013Co-Authors: Melissa L Harris, Lukas Sommer, Olga Shakhova, Kristina Buac, Ramin M Hakami, William J PavanAbstract:During embryogenesis, the transcription factor, SOX10, drives the survival and differentiation of the melanocyte lineage. However, the role that SOX10 plays in postnatal melanocytes is not established. We show in vivo that melanocyte stem cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs remain undifferentiated. SOX10 knockout (SOX10(fl); Tg(Tyr::CreER)) results in loss of both McSCs and differentiated melanocytes, while overexpression of SOX10 (Tg(DctSOX10)) causes premature differentiation and loss of McSCs, leading to hair graying. This suggests that levels of SOX10 are key to normal McSC function and SOX10 must be downregulated for McSC establishment and maintenance. We examined whether the mechanism of Tg(DctSOX10) hair graying is through increased expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf (Mitf(vga9) ) can rescue hair graying in Tg(DctSOX10) animals. Surprisingly, Mitf(vga9) does not mitigate but exacerbates Tg(DctSOX10) hair graying suggesting that MITF participates in the negative regulation of SOX10 in McSCs. These observations demonstrate that while SOX10 is necessary to maintain the postnatal melanocyte lineage it is simultaneously prevented from driving differentiation in the McSCs. This data illustrates how tissue-specific stem cells can arise from lineage-specified precursors through the regulation of the very transcription factors important in defining that lineage.
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sox proteins in melanocyte development and melanoma
Pigment Cell & Melanoma Research, 2010Co-Authors: Melissa L Harris, Laura L Baxter, Stacie K Loftus, William J PavanAbstract:Over 10 years have passed since the first Sox gene was implicated in melanocyte development. Since then, we have discovered that SOX5, SOX9, SOX10 and SOX18 all participate as transcription factors that affect key melanocytic genes in both regulatory and modulatory fashions. Both SOX9 and SOX10 play major roles in the establishment and normal function of the melanocyte; SOX10 has been shown to heavily influence melanocyte development and SOX9 has been implicated in melanogenesis in the adult. Despite these advances, the precise cellular and molecular details of how these SOX proteins are regulated and interact during all stages of the melanocyte life cycle remain unknown. Improper regulation of SOX9 or SOX10 is also associated with cancerous transformation, and thus understanding the normal function of SOX proteins in the melanocyte will be key to revealing how these proteins contribute to melanoma.
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an evolutionarily conserved intronic region controls the spatiotemporal expression of the transcription factor SOX10
BMC Developmental Biology, 2008Co-Authors: William J Pavan, Thomas J Carney, James R Dutton, Anthony Antonellis, Frederico S L M Rodrigues, Andrew Ward, Robert N. KelshAbstract:Background A major challenge lies in understanding the complexities of gene regulation. Mutation of the transcription factor SOX10 is associated with several human diseases. The disease phenotypes reflect the function of SOX10 in diverse tissues including the neural crest, central nervous system and otic vesicle. As expected, the SOX10 expression pattern is complex and highly dynamic, but little is known of the underlying mechanisms regulating its spatiotemporal pattern. SOX10 expression is highly conserved between all vertebrates characterised.
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deletion of long range sequences at SOX10 compromises developmental expression in a mouse model of waardenburg shah ws4 syndrome
Human Molecular Genetics, 2006Co-Authors: Anthony Antonellis, Robert N. Kelsh, William Bennett, Trevelyan R Menheniott, Arjun B Prasad, Shih Queen Leelin, Eric D Green, Derek Paisley, William J PavanAbstract:The transcription factor SOX10 is mutated in the human neurocristopathy Waardenburg-Shah syndrome (WS4), which is characterized by enteric aganglionosis and pigmentation defects. SOX10 directly regulates genes expressed in neural crest lineages, including the enteric ganglia and melanocytes. Although some SOX10 target genes have been reported, the mechanisms by which SOX10 expression is regulated remain elusive. Here, we describe a transgene-insertion mutant mouse line (Hry) that displays partial enteric aganglionosis, a loss of melanocytes, and decreased SOX10 expression in homozygous embryos. Mutation analysis of SOX10 coding sequences was negative, suggesting that non-coding regulatory sequences are disrupted. To isolate the Hry molecular defect, SOX10 genomic sequences were collected from multiple species, comparative sequence analysis was performed and software was designed (ExactPlus) to identify identical sequences shared among species. Mutation analysis of conserved sequences revealed a 15.9 kb deletion located 47.3 kb upstream of SOX10 in Hry mice. ExactPlus revealed three clusters of highly conserved sequences within the deletion, one of which shows strong enhancer potential in cultured melanocytes. These studies: (i) present a novel hypomorphic SOX10 mutation that results in a WS4-like phenotype in mice; (ii) demonstrate that a 15.9 kb deletion underlies the observed phenotype and likely removes sequences essential for SOX10 expression; (iii) combine a novel in silico method for comparative sequence analysis with in vitro functional assays to identify candidate regulatory sequences deleted in this strain. These studies will direct further analyses of SOX10 regulation and provide candidate sequences for mutation detection in WS4 patients lacking a SOX10-coding mutation.
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analysis of SOX10 function in neural crest derived melanocyte development SOX10 dependent transcriptional control of dopachrome tautomerase
Developmental Biology, 2001Co-Authors: Brian S Potterf, Ramin Mollaaghababa, Ling Hou, Michelle E Southardsmith, Thomas J Hornyak, Heinz Arnheiter, William J PavanAbstract:SOX10 is a high-mobility-group transcription factor that plays a critical role in the development of neural crest-derived melanocytes. At E11.5, mouse embryos homozygous for the SOX10(Dom) mutation entirely lack neural crest-derived cells expressing the lineage marker KIT, MITF, or DCT. Moreover, neural crest cell cultures derived from homozygous embryos do not give rise to pigmented cells. In contrast, in SOX10(Dom) heterozygous embryos, melanoblasts expressing KIT and MITF do occur, albeit in reduced numbers, and pigmented cells eventually develop in nearly normal numbers both in culture and in vivo. Intriguingly, however, SOX10(Dom)/+ melanoblasts transiently lack Dct expression both in culture and in vivo, suggesting that during a critical developmental period SOX10 may serve as a transcriptional activator of Dct. Indeed, we found that SOX10 and DCT colocalized in early melanoblasts and that SOX10 is capable of transactivating the Dct promoter in vitro. Our data suggest that during early melanoblast development SOX10 acts as a critical transactivator of Dct, that MITF, on its own, is insufficient to stimulate Dct expression, and that delayed onset of Dct expression is not deleterious to the melanocyte lineage.
