Delineating the role of MITF isoforms in pigmentation and tissue homeostasis

Abstract

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 the expression of these independent isoforms of MITF is regulated. Here, we show that melanocytes express two isoforms of MITF, MITF‐A and MITF‐M. The 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.

User guide to MiT‐TFE isoforms and post‐translational modifications

“…Despite being detected in many cell lines, MITF-C is not found in cells of the melanocyte-lineage (Fuse et al, 1999). in RPE and iris (Flesher et al, 2020). Surprisingly, both Mitf-M knockout mice and Mitf-A overexpressing mice showed enlarged kidneys (Flesher et al, 2020;Phelep et al, 2017).…”

“…The functional role of the different MITF isoforms has not been fully investigated. Isoform‐specific knockouts showed that mice lacking Mitf‐M do not have melanocytes in the epidermis, hair follicle, iris, and choroid, whereas there was no change of pigmentation in RPE and iris (Flesher et al., 2020). Surprisingly, both Mitf‐M knockout mice and Mitf‐A overexpressing mice showed enlarged kidneys (Flesher et al., 2020; Phelep et al., 2017).…”

“…Isoform‐specific knockouts showed that mice lacking Mitf‐M do not have melanocytes in the epidermis, hair follicle, iris, and choroid, whereas there was no change of pigmentation in RPE and iris (Flesher et al., 2020). Surprisingly, both Mitf‐M knockout mice and Mitf‐A overexpressing mice showed enlarged kidneys (Flesher et al., 2020; Phelep et al., 2017). Knocking out the Mitf‐A isoform only resulted in minor changes in melanin accumulation in the hair, reduced expression of Tyrosinase in the eye, and reduced number of nephrons (Flesher et al., 2020; Phelep et al., 2017).…”

“…Surprisingly, both Mitf‐M knockout mice and Mitf‐A overexpressing mice showed enlarged kidneys (Flesher et al., 2020; Phelep et al., 2017). Knocking out the Mitf‐A isoform only resulted in minor changes in melanin accumulation in the hair, reduced expression of Tyrosinase in the eye, and reduced number of nephrons (Flesher et al., 2020; Phelep et al., 2017). Clearly, the M‐isoform is critical for pigmentation whereas the A isoform plays a limited role for this phenotype.…”

Characterization of POU2F1 Gene and Its Potential Impact on the Expression of Genes Involved in Fur Color Formation in Rex Rabbit

“…Briefly, the relative quantity and distribution of melanocyte products, such as eumelanin and pheomelanin, determine the fur color [4,5]. It has been reported that gene expression affects the pigmentation of rabbit fur through various mechanisms; for example, some genes, such as SLC7A11 [6][7][8], melanocortin receptor 1 (MC1R) [9][10][11], microphthalmia-associated transcription factor (MITF) [12], and ASIP [13], are likely to influence the production and deposition of melanin.…”