The transcription factor Sox5 modulates Sox10 function during melanocyte development

Stolt, C. Claus; Lommes, Petra; Hillgärtner, Simone; Wegner, Michael

doi:10.1093/nar/gkn527

Cited by 84 publications

(90 citation statements)

References 56 publications

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“…The Ednrb2 probe was cloned from a cDNA library of E4 chick embryo using the following primers: 5¢-ATGACTCGAGGC-CTCTGAACAGAAATCCAG-3¢ and 5¢-TATCGGATCCTCTCATCTGTTGGCGTGATG-3¢. Mouse probes used were Mitf, Kit, Trp2 (Stolt et al, 2008).…”

Section: Immunohistochemistry and In Situ Hybridizationmentioning

confidence: 99%

A dynamic code of dorsal neural tube genes regulates the segregation between neurogenic and melanogenic neural crest cells

Nitzan¹,

Krispin²,

Pfaltzgraff

et al. 2013

Development

104

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SUMMARYUnderstanding when and how multipotent progenitors segregate into diverse fates is a key question during embryonic development. The neural crest (NC) is an exemplary model system with which to investigate the dynamics of progenitor cell specification, as it generates a multitude of derivatives. Based on 'in ovo' lineage analysis, we previously suggested an early fate restriction of premigratory trunk NC to generate neural versus melanogenic fates, yet the timing of fate segregation and the underlying mechanisms remained unknown. Analysis of progenitors expressing a Foxd3 reporter reveals that prospective melanoblasts downregulate Foxd3 and have already segregated from neural lineages before emigration. When this downregulation is prevented, late-emigrating avian precursors fail to upregulate the melanogenic markers Mitf and MC/1 and the guidance receptor Ednrb2, generating instead glial cells that express P0 and Fabp. In this context, Foxd3 lies downstream of Snail2 and Sox9, constituting a minimal network upstream of Mitf and Ednrb2 to link melanogenic specification with migration. Consistent with the gain-of-function data in avians, loss of Foxd3 function in mouse NC results in ectopic melanogenesis in the dorsal tube and sensory ganglia. Altogether, Foxd3 is part of a dynamically expressed gene network that is necessary and sufficient to regulate fate decisions in premigratory NC. Their timely downregulation in the dorsal neural tube is thus necessary for the switch between neural and melanocytic phases of NC development.

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Section: Immunohistochemistry and In Situ Hybridizationmentioning

confidence: 99%

A dynamic code of dorsal neural tube genes regulates the segregation between neurogenic and melanogenic neural crest cells

Nitzan¹,

Krispin²,

Pfaltzgraff

et al. 2013

Development

104

View full text Add to dashboard Cite

show abstract

“…It is also notable that one of the top 6-mers (ranked fourth) is predicted to bind PAX3, a key regulator of melanocyte differentiation (Lang et al 2005) which can cause Waardenburg syndrome type 1 and type 3 when mutated (OMIM:193500 and OMIM:148820, respectively). In addition, CREB1, SOX5, and RUNX-family TFs (predicted to bind 6-mers ranked fifth, eighth, and ninth, respectively) have been shown to play roles in regulating gene expression in melanocytes (Tada et al 2002;Raveh et al 2005;Saha et al 2006;Kingo et al 2008;Stolt et al 2008;Kanaykina et al 2010;Mizutani et al 2010).…”

Section: Machine Learning Reveals Sequence Features That Underlie Melmentioning

confidence: 99%

Integration of ChIP-seq and machine learning reveals enhancers and a predictive regulatory sequence vocabulary in melanocytes

et al. 2012

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We take a comprehensive approach to the study of regulatory control of gene expression in melanocytes that proceeds from large-scale enhancer discovery facilitated by ChIP-seq; to rigorous validation in silico, in vitro, and in vivo; and finally to the use of machine learning to elucidate a regulatory vocabulary with genome-wide predictive power. We identify 2489 putative melanocyte enhancer loci in the mouse genome by ChIP-seq for EP300 and H3K4me1. We demonstrate that these putative enhancers are evolutionarily constrained, enriched for sequence motifs predicted to bind key melanocyte transcription factors, located near genes relevant to melanocyte biology, and capable of driving reporter gene expression in melanocytes in culture (86%; 43/50) and in transgenic zebrafish (70%; 7/10). Next, using the sequences of these putative enhancers as a training set for a supervised machine learning algorithm, we develop a vocabulary of 6-mers predictive of melanocyte enhancer function. Lastly, we demonstrate that this vocabulary has genome-wide predictive power in both the mouse and human genomes. This study provides deep insight into the regulation of gene expression in melanocytes and demonstrates a powerful approach to the investigation of regulatory sequences that can be applied to other cell types.

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“…8 To address the relevance of these findings for human melanoma, we assessed whether in analogy to the mouse model, decreasing levels of SOX10 in human melanoma cell lines would interfere with melanoma maintenance. To this end, we performed RNA interference (RNAi)-mediated silencing of SOX10 in human melanoma cell lines 30 . In two distinct cell lines, SOX10 shRNA resulted in efficient downregulation of SOX10 expression, as revealed both by Western blot analysis and immunocytochemistry ( Supplementary Fig.…”

mentioning

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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The transcription factor Sox5 modulates Sox10 function during melanocyte development

Cited by 84 publications

References 56 publications

A dynamic code of dorsal neural tube genes regulates the segregation between neurogenic and melanogenic neural crest cells

A dynamic code of dorsal neural tube genes regulates the segregation between neurogenic and melanogenic neural crest cells

Integration of ChIP-seq and machine learning reveals enhancers and a predictive regulatory sequence vocabulary in melanocytes

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

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