Mutation of the Sry-related
            <i>Sox10</i>
            gene in
            <i>Dominant megacolon</i>
            , a mouse model for human Hirschsprung disease

Herbarth, Beate; Pingault, Véronique; Bondurand, Nadège; Kuhlbrodt, Kirsten; Hermans‐Borgmeyer, Irm; Puliti, Aldamaria; Lemort, N; Goossens, Michel; Wegner, Michael

doi:10.1073/pnas.95.9.5161

Cited by 339 publications

(256 citation statements)

References 30 publications

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“…Sox10 encodes an SRY-related HMG domain protein that is widely expressed in most neural-crest precursors. Its absence results in multiple neural crest-derived defects, including aganglionosis of the whole gut [10][11][12] . Haploinsufficiency of SOX10 in mice and individuals with HSCR results in aganglionosis of the hindgut [10][11][12][13][14][15] .…”

Section: E T T E R Smentioning

confidence: 99%

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

et al. 2004

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Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by the absence of neural crest-derived enteric ganglia in the colon 1 . One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB) 2,3 . The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon 4 . In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon. We identified binding sites for SOX10, an SRY-related transcription factor associated with HSCR 5 , in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.Mice and individuals with HSCR with mutations in the EDNRB-mediated pathway have megacolon because of the absence of enteric neurons in the distal gut 1 . This regional specificity of aganglionosis could be explained by a temporal requirement for Ednrb between embryonic day (E) 11 and E12.5 (ref. 4), when vagal neural crest-derived ENS progenitors are populating the hindgut during mouse embryogenesis, such that in the absence of EDNRB the migratory wavefront is delayed near the ileocecal junction (Fig. 1a) [6][7][8] . To elucidate the molecular mechanisms for Ednrb expression in the ENS, we dissected the Ednrb genomic region. We isolated a 78-kb P1 genomic clone encompassing Ednrb (Fig. 1b) and used it to create four independent transgenic lines. When we crossed the individual transgenic lines into the Ednrb-null mice, all the lines rescued postnatal death from megacolon (Fig. 1c). Although three of the lines did not rescue the melanocyte defect in the Ednrb-null mice (Fig. 1c), one line (when homozygous with respect to the transgene) partially rescued the pigmentation defect that resembles the hypomorphic Ednrb s allele 9 (data not shown). These results suggested that the P1 clone contained the necessary information for expression of Ednrb in ENS progenitors. In addition, we mapped a main transcription start site Ednrb -/-Tg P5

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Section: E T T E R Smentioning

confidence: 99%

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

et al. 2004

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“…SOX10 dom Inhibits Activation of the M-MITF Promoter-To examine the specificity of SOX10 in the cAMP responsiveness of the M-MITF reporter, we utilized a naturally occurring SOX10 mutant called Sox10 dom . Mice engineered with this mutant Sox10 allele exhibit a phenotype consistent with the human disease Waardenburg syndrome type 4, displaying significant melanocyte defects (21,22). Due to the insertion of a G nucleotide, which results in frameshift and concomitant premature stop codon, the mutated SOX10 dom allele has an intact high mobility group domain DNA-binding motif but lacks the C-terminal transactivation domain (Fig.…”

Section: Creb-mediated Transcriptional Activation Of the Mitfmentioning

confidence: 99%

A Tissue-restricted cAMP Transcriptional Response

Huber

Price

Widlund

et al. 2003

Journal of Biological Chemistry

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“…Absence of Sox10 affects NCSC survival and leads, therefore, to a loss of neural crest derivatives, including melanocytes 6,7,17 . In mice heterozygous for Sox10 null mutations, however, 5 most neural crest derivatives are properly generated during development, although neural crest stem and progenitor cell maintenance, proliferation, and fate decisions are impaired 6,9,[18][19][20][21][22] . In particular, both in human and mice, Sox10 haploinsufficiency is compatible with normal melanocyte specification and differentiation, but interferes with the generation of proper pigment cell numbers during development, leading to characteristic pigmentation defects at birth.…”

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confidence: 99%

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma

et al. 2012

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Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10, a transcription factor crucial for the formation of melanocytes from the neural crest. Strikingly, Sox10 haploinsufficiency counteracts Nras(Q61K)-driven congenital naevus and melanoma formation without affecting the physiological functions of neural crest derivatives in the skin. Moreover, Sox10 is also crucial for the maintenance of neoplastic cells in vivo. In human patients, virtually all congenital naevi and melanomas are SOX10 positive. Furthermore, SOX10 silencing in human melanoma cells suppresses neural crest stem cell properties, counteracts proliferation and cell survival, and completely abolishes in vivo tumour formation. Thus, SOX10 represents a promising target for the treatment of congenital naevi and melanoma in human patients.

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Mutation of the Sry-related Sox10 gene in Dominant megacolon , a mouse model for human Hirschsprung disease

Cited by 339 publications

References 30 publications

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

A Tissue-restricted cAMP Transcriptional Response

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma

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