alpha-melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome

The pituitary peptide alpha-melanocyte-stimulating hormone (alpha-MSH) stim ulates melanocytes to up-regulate cAMP, but the downstream targets of cAMP are not well understood mechanistically. One consequence of alpha-MSH stimu lation is increased melanization attributable to induction of pigmentation enzymes, including tyrosinase, which catalyzes a rate-limiting step in mela nin synthesis. The tyrosinase promoter is a principle target of the melanoc yte transcription factor Microphthalmia (Mi), a factor for which deficiency in humans causes Waardenburg syndrome II. We show here that both alpha-MSH and forskolin, a drug that increases cAMP, stimulate a rapid increase in M i mRNA and protein levels in both melanoma cell lines and primary melanocyt es. This up-regulation requires a cAMP-responsive element within the Mi pro moter, and the pathway leading to Mi stimulation is subject to tight homeos tatic regulation. Although cAMP signaling is ubiquitous, the Mi promoter wa s seen to be cAMP-responsive in melanocytes but not in non-melanocytes. Mor eover, dominant negative interference with Mi impeded successful alpha-MSH stimulation of tyrosinase, The regulation of Mi expression via alpha-MSH th us provides a direct mechanistic link to pigmentation. In addition, because the human melanocyte and deafness condition Waardenburg syndrome is someti mes caused by haploinsufficiency of Mi, its modulation by alpha-MSH suggest s therapeutic strategies targeted at up-regulating the remaining wild type Mi allele.