MITF-M-regulated melanocyte development

Melanocytes are cells that possess specialized organelles called melanosomes that synthesize eumelanin and pheomelanin from tyrosine in a series of reactions. Melanosomes are transferred from cutaneous melanocytes to adjacent keratinocytes to provide protection against UV as well as coloration of skin, eye, hair, feathers and scales. Besides being found in the basal layer of the skin, melanocytes are also present in hair follicles, the inner ear and in the iris eye, among other places. The eye also contains a layer of melanosome-containing cells behind the retina, called the retinal pigment epithelium (RPE) (reviewed in Mort et al, 2015; D'Mello et al, 2016; Goding and Arnheiter, 2019; Le et al, 2021; Cui and Man, 2023).

Cutaneous melanocytes and their precursors, melanoblasts, arise during embryogenesis from neural crest cells that migrate dorsolaterally through the developing embryo (reviewed in Mort et al, 2015). They also arise from glial/melanoblast precursors migrating on a ventromedial pathway and along nerves. Expression of MITF is a key determinant of melanocyte fate, and mutations in MITF are associated with a variety of defects in pigmentation as well as with deafness (due to absence of melanocytes in the inner ear) and microphthalmia (due to aberrant development of retina and RPE), among other conditions (reviewed in White and Zon, 2008; Mort et al, 2015; Goding and Arnheiter, 2019; Le et al, 2021).

The gene for MITF encodes several distinct isoforms based on alternative splicing. The gene has a 3' portion consisting of exons 2-9 that are generally shared by all transcripts. In mice and humans, the upstream region of the gene contains 9 exons, some of them coding, some not, and each regulated by its own promoter. Most of them are spliced to exon 2 via a common exon 1B. An exception is exon 1M which is directly spliced to exon 2, giving rise to the so-called M-isoform of MITF. This arrangement gives rise to a number of different mRNA and protein isoforms with preferential expression patterns. Exon 1A-containing transcripts, for instance, are ubiquitously expressed, exon 1H-containing transcripts are highly expressed in the heart, exon 1D-containing transcripts are expressed in the RPE, and exon 1M-containing transcripts are expressed in neural crest-derived melanocytes. Nevertheless, there is little information on whether the different isoforms have different functions except that exon 1B-containing transcripts (but not MITF-M) harbor a sequence subject to mTORC1 regulation (reviewed in Goding and Arnheiter, 2019; Vu et al, 2020). Most if not all transcripts come in two additional splice versions, one including and one excluding 18 bp of part of exon 6, called exon 6A, which encodes 6 amino acids lying upstream of the DNA-binding domain and which is regulated by MAPK signaling. They are usually referred to as the (+) and (-) versions of MITF. While the (-) version of a fragment of MITF-M has slightly reduced DNA-binding affinity compared to the (+) version, no specific role has so far been found for exon 6A. Cell-based assays suggest that MITF (+) has a strong inhibitory effect on cellular proliferation relative to the (-) version, and MITF (-) is expressed at high levels in melanoma cells.

This pathway focuses on the activity of the melanocyte lineage-specific transcription factor MITF-M, although some of the biology described may also be relevant for other MITF isoforms.