Transcriptional regulation of mitfa accounts for the sox10 requirement in zebrafish melanophore development

Mitfa is the master regulator of melanocyte fate.

“Mitfa is thus dubbed the ‘master regulator’ of melanocyte fate choice [13, 21, 25].”

Mitfa is necessary and sufficient to upregulate numerous melanocyte differentiation genes, including those controlling melanin synthesis.

“Like its mammalian counterpart, MITF, Mitfa has been proven necessary and sufficient to upregulate numerous melanocyte differentiation genes, including those controlling melanin synthesis (e.g. dct, silva and tyrosinase).”

Sox10, in conjunction with Wnt signalling, is required to activate and maintain mitfa transcription.

“In this lineage, Sox10, in conjunction with Wnt signalling, is required to activate and maintain mitfa transcription [13, 20, 24–26].”

Mitfa is able to efficiently rescue melanocyte development in the absence of sox10 through triggering both an Mitfa autoregulatory feedback loop and expression of melanocyte differentiation genes.

“For example, Mitfa is able to efficiently rescue melanocyte development in the absence of sox10 through triggering both an Mitfa autoregulatory feedback loop and expression of melanocyte differentiation genes [13, 25].”

sox10 is required for mitfa expression in late Cbls, and mitfa can promote melanocyte fate in the absence of sox10 if misexpressed.

“Furthermore, this requirement of pigment cells for sox10 manifests itself apparently in different ways; sox10 is required for mitfa expression in late Cbls, and mitfa can promote melanocyte fate in the absence of sox10 if misexpressed [25].”

Previously published experimental data show that maintenance of mitfa is restricted to melanocytes.

“These predictions are in contrast to previously published experimental data, showing that maintenance of mitfa is restricted to melanocytes [21], [22], although lower level mitfa expression has been detected by RNA-seq in differentiated iridophores [48].”

In all three models, expression of mitfa was predicted to be upregulated and then maintained in the iridophore lineage.

“In all three models, expression of the melanocyte marker, mitfa, a direct target of Sox10 [21], was predicted to be upregulated and then maintained in the iridophore lineage (Fig 5D–5F).”

Sox10 binds directly to the promoter of mitfa in zebrafish and activates its expression.

“Sox10 has been previously shown to bind directly to the promoter of mitfa in zebrafish, and to activate its expression [21], we thus include that interaction.”

All three models predict failure to upregulate mitfa and pnp4a upon loss of Sox10 function.

“Likewise, they appropriately predict the failure to upregulate both mitfa [21] and pnp4a (Fig 4K).”