Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges

Abstract

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.

Intermediate Cells of Dual Embryonic Origin Follow a Basal to Apical Gradient of Ingression Into the Lateral Wall of the Cochlea

“…MITF expression in a number of Schwann cell precursors in the ganglion is consistent with the idea of these cells adopting a melanoblast fate before migrating into the otic vesicle. Our observations are consistent with reports from Kaucka et al, who in addition to MITF positive cells migrating both from the neural crest and from the VIIIth ganglion, also described melanocytic cells migrating into the otic vesicle posteriorly from the IX and X cranial nerves ( Kaucka et al, 2021 ). As the cochlea begins to elongate, Schwann cell precursors keep coalescing around the neurons of the VIIIth to form glia, and some differentiate into melanocytes.…”

“…Similarly, single cell analysis of cochlear Plp1 positive embryonic ganglion cells found clusters expressing melanocyte markers (Tasdemir-Yilmaz et al, 2021). Finally, Kaucka et al reported that nerve associated Schwan cell precursors contribute extracutaneous melanocytes to the heart, meninges and supraorbital locations amongst others (Kaucka et al, 2021). Our data suggests that pigmented cells in the inner ear arise both through melanoblast precursors from neural crest migrating dorsolaterally under the dermis, and also from Schwann cell precursors associated with the cochleovestibular ganglion.…”

“…Recent findings have shown that there is contribution of Schwann cell precursors on the peripheral nerves to extracutaneous melanocytes such as the melanocytes of the inner ear ( Bonnamour et al, 2021 ; Kaucka et al, 2021 ). Bonnamour and colleagues used a Dhh-Cre line to genetically trace Schwann cell precursors in the inner ear and found that up to 90% of the intermediate cells of the stria vascularis were labeled by Dhh tracing.…”

“…Although these neural crest contributions in the inner ear have been known for some time, the timing of how these cells migrate and how they differentiate in their proper locations during development was not known. In addition, new data has revealed that pigmented cells in the cochlea can originate from Schwann cell precursors ( Bonnamour et al, 2021 ; Kaucka et al, 2021 ). In this study we characterized the temporal migration of melanoblasts into the inner ear, their dual embryonic origin, their proliferation, morphological maturation, and the subsequent postnatal differentiation into intermediate cells.…”

Cell Fate Decisions in the Neural Crest, from Pigment Cell to Neural Development

“…differentiated states are under active maintenance by local signals. Under this view, we can consider that SCPs, which have been shown to be multipotent NCSCs [86,88,[152][153][154], and other NCSCs are NC-HMPs that have a histological and molecular phenotype driven by the local niche (e.g., for SCP, including the neuronal axon; [87]); consistent with this, the transcriptomic signature of SCPs and NCCs in mice are remarkably similar [38]. Release from that niche (e.g., when SCPs disperse from the axons; [86]) results in a change in the GRN state so that the NC-HMP resumes its fate sub-state cycling mode; this might be a key aspect of stem cell activation.…”