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

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

Stable Identifier

R-HSA-9856649

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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

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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).

Literature References

PubMed ID	Title	Journal	Year
25670789	The melanocyte lineage in development and disease Jackson, IJ, Patton, EE, Mort, RL	Development	2015
18068699	colgate/hdac1 Repression of foxd3 expression is required to permit mitfa-dependent melanogenesis Henion, PD, El-Hodiri, HM, Ignatius, MS, Moose, HE	Dev Biol	2008
18786412	Melanocytes in development, regeneration, and cancer White, RM, Zon, LI	Cell Stem Cell	2008
37770430	Acetylation reprograms MITF target selectivity and residence time Mazza, D, Patton, EE, Filippakopoulos, P, Lashgari, A, Goding, CR, Louphrasitthiphol, P, Thomas, B, Friedrichsen, H, Pogenberg, V, Schepsky, A, Picaud, S, Lambert, JP, Loffreda, A, Wilmanns, M, Zeng, Z, Steingrímsson, E	Nat Commun	2023
22186729	Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest Favaro, R, Ernfors, P, Kitambi, SS, Lallemend, F, Zaitoun, I, Suter, U, Furlan, A, Birchmeier, C, Nicolis, S, Müller, T, Blanchart, A, Takahashi, Y, Zinin, N, Aranda, S, Lübke, M, Adameyko, I	Development	2012
21909283	An iterative genetic and dynamical modelling approach identifies novel features of the gene regulatory network underlying melanocyte development Kelsh, RN, Vibert, L, Rocco, A, Greenhill, ER, Nikaido, M	PLoS Genet	2011
19527705	Foxd3 controls melanophore specification in the zebrafish neural crest by regulation of Mitf Raible, DW, Lister, JA, Curran, K	Dev Biol	2009
31123060	MITF-the first 25 years Arnheiter, H, Goding, CR	Genes Dev	2019
23858437	Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3 Kalcheim, C, Nitzan, E, Pfaltzgraff, ER, Labosky, PA	Proc Natl Acad Sci U S A	2013
32531202	Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution Mazza, D, Patton, EE, Lu, M, Siddaway, R, Filippakopoulos, P, Goding, CR, Louphrasitthiphol, P, Schuster-Böckler, B, Thomas, B, Friedrichsen, H, Pogenberg, V, Schepsky, A, Lambert, JP, Middleton, M, Davidson, I, Freter, R, Loffreda, A, Lu, X, Wilmanns, M, Suer, E, Strub, T, Zeng, Z, Steingrímsson, E, Lisle, R	Mol Cell	2020
20460180	Interplay between Foxd3 and Mitf regulates cell fate plasticity in the zebrafish neural crest Prendergast, A, Raible, DW, Parichy, DM, Kunkel, GR, Lister, JA, Curran, K	Dev Biol	2010
23615280	A dynamic code of dorsal neural tube genes regulates the segregation between neurogenic and melanogenic neural crest cells Krispin, S, Kalcheim, C, Klar, A, Nitzan, E, Pfaltzgraff, ER, Labosky, PA	Development	2013