Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

Abstract

The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while the second wave of melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts but led to marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. Furthermore, in vitro hyperactivation of the Wnt/β-catenin pathway, which is required for melanocyte development, induces activation of Mitf-M, in turn repressing FoxD3 expression. In conclusion, β-catenin overexpression promotes SCP cell fate decisions towards the melanocyte lineage.

Uncovering Minimal Pathways in Melanoma Initiation

“…We then subsetted the cells in all samples that were judged to have a potential lineage relationship to melanocytes. These included melanocytes themselves, Schwann cells (neural crest-derived cells thought to share a common precursor with melanocytes 40,41 ), and any cell types in which we could document recombination driven by the Tyr-Cre ERT2 transgene (in a subset of samples, the mTmG reporter system 42 was used so that expression of GFP marked some of the cells in which Cre-mediated recombination had occurred); the latter included the abundant cell type in tumor samples that expressed melanoma markers. These 35,527 cells, which we refer to as "neural crest derived", were re-normalized using ScTransform and subclustered (Fig 2C).…”

NR2F1 regulates a Schwann cell precursor‐vs‐melanocyte cell fate switch in a mouse model of Waardenburg syndrome type IV

“…The co‐expression of NR2F1 and SOX10 in e12.5 nerve‐associated SCPs further support this idea (Figure 4). Based on their ability to repress canonical WNT/βCatenin signaling in different contexts (Faedo et al, 2008; Tong et al, 2014), it is also tempting to speculate that NR2F1 and SOX10 might actively counteract melanocyte differentiation in SCPs via inhibition of the pro‐melanogenic WNT/βCatenin pathway (Colombo et al, 2022).…”

Advances and challenges in modeling inherited peripheral neuropathies using iPSCs

“…However, once SCPs dissociate from the peripheral nerve axons, they can differentiate into melanocytes via the upregulation of the cell fate determinant transcription factor microphthalmia (MITF) 52 . Separating the early melanocyte lineage, i.e., melanoblasts, from the Schwann cell lineage via in vitro differentiation protocols is difficult because their cell fate is regulated by the expression levels of common transcription factors, such as FOXD3 61 (reviewed in Van Raamsdonk & Deo 62 ), and pathways, such as the WNT/β-catenin pathway 63 . Similarly, early melanocyte lineage cells can express several Schwann cell proteins and RNA transcripts from genes such as ErbB3, P75, SOX10 64 , PLP1, and MBP (Golli-MBP RNA transcripts) 65,66 and have bi-and tripolar morphologies.…”