title: The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10.
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.
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors: Pooja
authors: P
authors: Agarwal
authors: Michael P
authors: MP
authors: Verzi
authors: Thuyen
authors: T
authors: Nguyen
authors: Jianxin
authors: J
authors: Hu
authors: Melissa L
authors: ML
authors: Ehlers
authors: David J
authors: DJ
authors: McCulley
authors: Shan-Mei
authors: SM
authors: Xu
authors: Evdokia
authors: E
authors: Dodou
authors: Joshua P
authors: JP
authors: Anderson
authors: Maria L
authors: ML
authors: Wei
authors: Brian L
authors: BL
authors: Black
references: Dev Biol. 1993 Sep;159(1):1-11
references: 8365553
references: Pigment Cell Res. 2004 Aug;17(4):352-62
references: 15250937
references: Development. 1989 Apr;105(4):707-14
references: 2557196
references: Genes Dev. 2001 Jan 1;15(1):66-78
references: 11156606
references: Hum Mol Genet. 2003 Apr 15;12(8):937-45
references: 12668617
references: Dev Biol. 2005 Jan 1;277(1):155-69
references: 15572147
references: Pigment Cell Res. 2004 Jun;17(3):215-24
references: 15140066
references: Curr Opin Genet Dev. 2006 Aug;16(4):360-6
references: 16793256
references: Genes Dev. 2004 Oct 1;18(19):2348-53
references: 15466486
references: Nat Genet. 1998 Jan;18(1):60-4
references: 9425902
references: Semin Cell Dev Biol. 2005 Dec;16(6):683-93
references: 16043371
references: J Invest Dermatol. 2007 Feb;127(2):421-8
references: 17068483
references: Am J Med Genet B Neuropsychiatr Genet. 2010 Jul;153B(5):1042-51
references: 20333642
references: J Med Genet. 2010 Jan;47(1):22-9
references: 19592390
references: Dev Dyn. 2009 Oct;238(10):2588-98
references: 19777593
references: Development. 2005 Aug;132(15):3405-17
references: 15987774
references: Development. 2004 Oct;131(19):4637-50
references: 15358668
references: Nat Genet. 2004 Apr;36(4):361-9
references: 15004559
references: Clin Genet. 2010 Nov;78(5):471-7
references: 20412115
references: Genes Dev. 2007 Feb 15;21(4):436-49
references: 17322403
references: Development. 2004 Aug;131(16):3931-42
references: 15253934
references: Development. 2010 May;137(9):1451-60
references: 20335356
references: Genome Res. 1999 Mar;9(3):215-25
references: 10077527
references: Annu Rev Cell Dev Biol. 2006;22:267-86
references: 16803431
references: Oncogene. 2003 May 19;22(20):3016-23
references: 12789276
references: Curr Opin Pediatr. 2000 Dec;12(6):610-7
references: 11106284
references: Development. 1998 Nov;125(22):4565-74
references: 9778514
references: Science. 1997 May 30;276(5317):1404-7
references: 9162005
references: Dev Biol. 2001 Sep 15;237(2):245-57
references: 11543611
references: Curr Opin Genet Dev. 2003 Jun;13(3):284-9
references: 12787791
references: Methods Mol Biol. 1997;67:141-9
references: 9031138
references: Development. 2005 Jun;132(12):2685-95
references: 15930108
references: Hum Mutat. 2010 Apr;31(4):391-406
references: 20127975
references: Mech Dev. 2003 Sep;120(9):1021-32
references: 14550531
references: Dev Cell. 2007 Apr;12(4):645-52
references: 17420000
references: Nucleic Acids Res. 2000 Aug 15;28(16):3047-55
references: 10931919
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5161-5
references: 9560246
references: Dev Biol. 2006 Jul 1;295(1):232-49
references: 16650841
references: J Neurosci. 1998 Jan 1;18(1):237-50
references: 9412504
references: Nat Rev Genet. 2002 Jun;3(6):453-61
references: 12042772
references: Curr Biol. 1998 Dec 3;8(24):1323-6
references: 9843687
references: Oncogene. 2003 May 19;22(20):3024-34
references: 12789277
references: FEBS Lett. 2004 Jan 2;556(1-3):236-44
references: 14706856
references: Virology. 2000 Aug 15;274(1):17-25
references: 10936084
references: Semin Cell Dev Biol. 2005 Dec;16(6):694-703
references: 16039883
references: Development. 2007 Dec;134(23):4131-40
references: 17959722
references: Neuropharmacology. 2000 Oct;39(13):2615-23
references: 11044731
references: Dev Biol. 1999 Jul 15;211(2):255-67
references: 10395786
references: Genesis. 2005 Sep;43(1):43-8
references: 16106363
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17067-72
references: 18955699
references: Development. 1994 May;120(5):1251-63
references: 8026334
references: Cell. 2008 Dec 12;135(6):1053-64
references: 19070576
references: Development. 1989 Nov;107(3):453-63
references: 2612372
references: Mech Dev. 1997 Dec;69(1-2):3-11
references: 9486527
references: J Hered. 1984 Nov-Dec;75(6):435-9
references: 6512238
references: Nat Genet. 1998 Feb;18(2):171-3
references: 9462749
references: Pediatr Dev Pathol. 1999 Nov-Dec;2(6):559-69
references: 10508880
references: Biochem Biophys Res Commun. 2001 Sep 21;287(2):493-500
references: 11554755