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PMID:21610032

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Citation

Agarwal, P, Verzi, MP, Nguyen, T, Hu, J, Ehlers, ML, McCulley, DJ, Xu, SM, Dodou, E, Anderson, JP, Wei, ML and Black, BL (2011) The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10. Development 138:2555-65

Abstract

Waardenburg syndromes are characterized by pigmentation and autosensory hearing defects, and mutations in genes encoding transcription factors that control neural crest specification and differentiation are often associated with Waardenburg and related disorders. For example, mutations in SOX10 result in a severe form of Waardenburg syndrome, Type IV, also known as Waardenburg-Hirschsprung disease, characterized by pigmentation and other neural crest defects, including defective innervation of the gut. SOX10 controls neural crest development through interactions with other transcription factors. The MADS box transcription factor MEF2C is an important regulator of brain, skeleton, lymphocyte and cardiovascular development and is required in the neural crest for craniofacial development. Here, we establish a novel role for MEF2C in melanocyte development. Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes. We identify a transcriptional enhancer of Mef2c that directs expression to the neural crest and its derivatives, including melanocytes, in transgenic mouse embryos. This novel Mef2c neural crest enhancer contains three functional SOX binding sites and a single essential MEF2 site. We demonstrate that Mef2c is a direct transcriptional target of SOX10 and MEF2 via this evolutionarily conserved enhancer. Furthermore, we show that SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit, suggesting that MEF2C might serve as a potentiator of the transcriptional pathways affected in Waardenburg syndromes.

Links

PubMed PMC3100711 Online version:10.1242/dev.056804

Keywords

Animals; Embryo, Mammalian; Gene Expression Regulation, Developmental; Melanocytes/cytology; Mice; Mice, Transgenic; Myogenic Regulatory Factors/physiology; Neural Crest/growth & development; SOXE Transcription Factors/physiology; Transcription, Genetic; Waardenburg's Syndrome/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TYRP2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SOX10

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CFN5

F

Seeded From UniProt

complete

MOUSE:SOX10

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SOX10

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SOX10

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MEF2C

involved_in

GO:0030318: melanocyte differentiation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8CFN5

P

Seeded From UniProt

complete

HUMAN:MEF2C

involved_in

GO:0014033: neural crest cell differentiation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8CFN5

P

Seeded From UniProt

complete

HUMAN:MEF2C

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8CFN5

F

Seeded From UniProt

complete

PONAB:MEF2C

involved_in

GO:0030318: melanocyte differentiation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8CFN5

P

Seeded From UniProt

complete

PONAB:MEF2C

involved_in

GO:0014033: neural crest cell differentiation

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8CFN5

P

Seeded From UniProt

complete

PONAB:MEF2C

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q8CFN5

F

Seeded From UniProt

complete

MOUSE:MEF2C

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0030318: melanocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0014033: neural crest cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0071837: HMG box domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04888

F

Seeded From UniProt

complete


See also

References

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