Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders.

Abstract

Waardenburg syndrome (WS) is an inherited sensorineural deafness condition in humans caused by melanocyte deficiencies in the inner ear and forelock. Mutation of microphthalmia-associated transcription factor (MITF) is known to produce WS type IIA whereas mutations of either endothelin (EDN) or its receptor endothelin receptor B (EDNRB) produce WS type IV. However, a link between MITF haploinsufficiency and EDN signaling has not yet been established. Here we demonstrate mechanistic connections between EDN and MITF and their functional importance in melanocytes. Addition of EDN to cultured human melanocytes stimulated the phosphorylation of MITF in an EDNRB-dependent manner, which was completely abolished by mitogen-activated protein kinase kinase inhibition. The expression of melanocyte-specific MITF mRNA transcripts was markedly augmented after incubation with EDN1 and was followed by increased expression of MITF protein. Up-regulated expression of MITF was found to be mediated via both the mitogen-activated protein kinase-p90 ribosomal S6 kinase-cAMP response element-binding protein (CREB) and cAMP-protein kinase A-CREB pathways. In addition, EDNRB expression itself was seen to be dependent on MITF. The functional importance of these connections is illustrated by the ability of EDN to stimulate expression of melanocytic pigmentation and proliferation markers in an MITF-dependent fashion. Collectively these data provide mechanistic and epistatic links between MITF and EDN/EDNRB, critical melanocytic survival factors and WS genes.

• Authors: Kayo Sato-Jin, Emi K Nishimura, Eijiro Akasaka, Wade Huber, Hajime Nakano, Arlo Miller, Jinyan Du, Min Wu, Katsumi Hanada, Daisuke Sawamura, David E Fisher, Genji Imokawa
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 22 Issue 4 Pg. 1155-68 (Apr 2008) ISSN: 1530-6860 [Electronic] United States
• PMID: 18039926 (Publication Type: Journal Article)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Endothelins
• Microphthalmia-Associated Transcription Factor
• Mitogen-Activated Protein Kinase 3

Topics

• Cyclic AMP Response Element-Binding Protein (metabolism)
• Endothelins (metabolism)
• Epistasis, Genetic
• Humans
• Melanocytes (metabolism)
• Microphthalmia-Associated Transcription Factor (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation
• Pigmentation Disorders (genetics, metabolism)
• Signal Transduction
• Waardenburg Syndrome (metabolism)