# Melanocyte differentiation and mechanosensation are differentially modulated by distinct extracellular matrix proteins

## TL;DR

This study shows how different extracellular matrix proteins affect melanocyte behavior, influencing their function and differentiation through specific signaling pathways.

## Contribution

The paper identifies MITF as an ECM- and mechanosensitive transcription factor in melanocytes, revealing distinct roles of collagen I and fibronectin in regulating melanocyte phenotypes.

## Key findings

- Collagen I promotes a differentiated melanocyte phenotype with high nuclear MITF and melanogenesis.
- Fibronectin induces a dedifferentiated, motile phenotype with reduced nuclear MITF and increased ERK activity.
- ECM-dependent mechanosensation highlights the context-specific regulation of melanocyte function.

## Abstract

Melanocyte dysfunctions can lead to pigmentation disorders or melanoma. Melanocytes interact context-dependently with various types of ECM, including collagens and fibronectin. Alterations in ECM composition and stiffness can impact cell behavior, but their specific roles for melanocyte functions remain unclear. We here exposed melanocytes to different ECM proteins and varying substrate stiffnesses, and identified MITF, a key regulator of melanocyte differentiation and function, as an ECM- and mechanosensitive transcription factor. Moreover, distinct ECM proteins and substrate stiffness engaged a FAK/MEK/ERK/MITF signaling axis to control melanocyte functions. Collagen I restricted FAK and ERK activation, promoting elevated nuclear MITF levels, melanocyte proliferation and a differentiated transcriptomic signature. Conversely, fibronectin elicited FAK and ERK activation, reduced nuclear MITF, increased motility and a dedifferentiated transcriptomic signature. On fibronectin, inhibiting MEK/ERK activity caused increased MITF nuclear localization and enhanced melanogenesis. Additionally, FAK inhibition reduced ERK activation and enhanced melanogenesis, supporting that FAK acts upstream of ERK. Finally, melanocytes show ECM-dependent mechanoresponses. In summary, extrinsic cues exert substantial effects on melanocyte function, involving ERK-dependent MITF regulation.

Distinct ECM components remodel melanocyte phenotypes, mechanosensation and transcriptomic program, partly through MITF modulation.

MITF has been identified as an ECM- and mechanosensitive transcription factor in melanocytes.Collagen I limits MEK/ERK activity, promoting high nuclear MITF and triggering a differentiated, pigmentated, proliferative phenotype.Fibronectin enhances MEK/ERK signaling, reducing nuclear MITF and melanin production, while inducing a dedifferentiated, motile phenotype.On fibronectin, FAK-driven ERK activation suppresses melanogenesis and MEK/ERK inhibition restores both MITF nuclear localization and melanogenesis.Melanocyte responses to substrate stiffness are ECM-dependent, highlighting the context-specificity of mechanosensation.

MITF has been identified as an ECM- and mechanosensitive transcription factor in melanocytes.

Collagen I limits MEK/ERK activity, promoting high nuclear MITF and triggering a differentiated, pigmentated, proliferative phenotype.

Fibronectin enhances MEK/ERK signaling, reducing nuclear MITF and melanin production, while inducing a dedifferentiated, motile phenotype.

On fibronectin, FAK-driven ERK activation suppresses melanogenesis and MEK/ERK inhibition restores both MITF nuclear localization and melanogenesis.

Melanocyte responses to substrate stiffness are ECM-dependent, highlighting the context-specificity of mechanosensation.

Distinct ECM components remodel melanocyte phenotypes, mechanosensation and transcriptomic program, partly through MITF modulation.