Delineating the Role of MITF Isoforms in Pigmentation and Tissue Homeostasis

MITF, a gene that is mutated in familial melanoma and Waardenburg syndrome, encodes multiple isoforms expressed from alternative promoters that share common coding exons but have unique amino termini. It is not completely understood how these isoforms influence pigmentation in different tissues and how expression of these independent isoforms of MITF are regulated. Here, we show that melanocytes express two isoforms of MITF, MITF-A and MITF-M. Expression of MITF-A is partially regulated by a newly identified retinoid enhancer element located upstream of the MITF-A promoter. Mitf-A knockout mice have only subtle changes in melanin accumulation in the hair and reduced Tyr expression in the eye. In contrast, Mitf-M null mice have enlarged kidneys, lack neural crest derived melanocytes in the skin, choroid, and iris stroma; yet maintain pigmentation within the retinal pigment epithelium and iris pigment epithelium of the eye. Taken together, these studies identify a critical role for MITF-M in melanocytes, a minor role for MITF-A in regulating pigmentation in the hair and Tyr expression in the eye, and a novel role for MITF-M in size control of the kidney. Sorted EGFP+ melanocytes and tdTomato+ other skin cells were isolated from ROSA, Tyr:Cre mice. Two mice were treated with UVB wavelength light and two mice were not exposed to UVB prior to collection. Standard RNA isolation protocols were used.