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

Marketa Kaucka,Bara Szarowska,Alberto Joven Araus,Polina Kameneva,Inga Schmidt,Maria Eleni Kastriti,Andras Simon,Jozef Kaiser,Michaela Kavkova,Igor Adameyko,Lucie Peskova

doi:10.1007/s00018-021-03885-9

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.

Highlights

Melanocytes inhabit the skin, hair follicles, and the iris of the eye [1,2,3,4]
We addressed the origin of extracutaneous melanocytes located in the heart, inner ear, brain meninges and other extracutaneous locations
We revealed that peripheral nerve-associated Schwann cell precursors (SCPs) are an essential source of extracutaneous melanocytes in all investigated locations, and the disruption of endothelin receptor B (EDNRB)/Endothelin 3 (EDN3) signaling results in the accumulation of nerve-associated melanoblasts not capable of leaving the nerves as well as dispersing into internal and external body locations

Summary

Introduction

Melanocytes inhabit the skin, hair follicles, and the iris of the eye [1,2,3,4]. These cells are responsible for the protection from UV radiation damage and provide colour to the skin or fur, which is crucial for various aspects of the animal’s life, including display and camouflage [4,5,6,7]. Melanocytes are present in locations deep inside the body that are not directly exposed to UV radiation These extracutaneous pigment cells are found in the stria vascularis of the inner ear, in the leptomeninges,. We revealed that peripheral nerve-associated SCPs are an essential source of extracutaneous melanocytes in all investigated locations, and the disruption of EDNRB/EDN3 signaling results in the accumulation of nerve-associated melanoblasts not capable of leaving the nerves as well as dispersing into internal and external body locations. This provides the first understanding of the molecular machinery and developmental context. We investigated the evolutionary conservation of extracutaneous melanocyte association with blood vessels and nerves in the inner organs across analyzed species

Results

X md OV

B Cerebrum brain meninges

Discussion