Transcriptional and post-translational regulation of MITF-M expression and activity

Transcriptional and post-translational regulation of MITF-M expression and activity Melanocytes, neurons and glia all arise from precursor cells derived from neural crest cells. Cells that will give rise to neurons and glia migrate away from the neural crest earlier and in a ventral pattern, while cells that will give rise to melanocytes leave the neural crest later and migrate dorsolaterally. Nevertheless, melanocytes can also arise in an alternate pathway from dual Schwann cell/melanocyte precursors or by dedifferentiation from Schwann cells, a derivative of the glial lineage (reviewed in Mort et al, 2015). MITF-M is a key regulator of melanocyte development, and its expression distinguishes the melanocyte fate from that of glial and neural cells. MITF-M expression is repressed in precursors through the activity of FOXD3 and SOX2. Depending on the species, these transcription factors may either bind directly to elements in the MITF-M promoter to repress transcription, or may act independently of DNA binding by disrupting protein-protein interactions that promote transcriptional activity (Nitzan et al, 2013a,b; Curran et al, 2009, 2010; Adameyko et al, 2012; reviewed in Mort et al, 2015; White and Zon, 2008; Goding and Arnheiter, 2019). FOXD3 and SOX2 expression, in turn, are regulated by a cascade of other transcription factors, including ZIC1, PAX3, SNAIL2 and SOX9 (reviewed in Mort et al, 2015; Goding and Arnheiter, 2019).
Relief of FOXD3 mediated repression may depend in part on HDAC1, as well as on down regulation of SNAIL2 (Ignatius et al, 2008; Greenhill et al, 2011; Nitzan et al, 2013a, b). MITF-M expression in unpigmented but committed melanoblasts depends on PAX3 and SOX10 binding at the promoter as well as on WNT, EDNRB and KIT signaling (reviewed in Mort et al, 2015; White and Zon, 2008; Goding and Arnheiter, 2019). Initial expression of MITF-M also contributes to downregulation of FOXD3 and SOX2 establishing a positive feedback loop that reinforces commitment to the melanocyte fate (reviewed in Mort et al, 2015; Goding and Arnheiter, 2019).
In addition to transcriptional regulation, MITF-M activity is also controlled by post translational modifications, although the significance of these modifications is not always clear. SUMOylation, ubiquitination and phosphorylation downstream of MAPK, WNT and AKT signaling can all impact the stability, localization or activity of MITF-M (reviewed in Goding and Arnheiter, 2019), and acetylation regulates the occupancy of target promoters, decreasing occupancy at differentiation-specific promoters (Louphrasitthiphol et al, 2020, 2023).