# Loss-of-function mutations in the melanocortin-2-receptor (mc2r) lead to skin hyperpigmentation in teleost fish

## TL;DR

This study shows that a specific receptor in fish, when mutated, causes increased skin pigmentation and affects hormone production.

## Contribution

The study reveals a novel role of the melanocortin-2-receptor in pigment cell development and metabolic regulation in zebrafish.

## Key findings

- Loss-of-function mutations in mc2r lead to hyperpigmentation in zebrafish.
- mc2r knockout zebrafish show impaired interrenal steroidogenesis and increased melanophores and xanthophores.
- Transcriptomic analysis shows upregulation of genes related to melanin synthesis and lipid metabolism.

## Abstract

Melanocortins regulate pigmentation via melanocortin receptors (MCRs), which are highly conserved across vertebrates. Unlike other MCRs, the melanocortin 2 receptor (MC2R) is exclusively activated by ACTH; however, its role in pigmentation remains unclear. Using CRISPR/Cas9-generated mc2r knockout zebrafish, we demonstrated that the loss of mc2r in zebrafish results in impaired interrenal steroidogenesis and pronounced hyperpigmentation characterized by an increased number of melanophores and xanthophores while preserving normal patterning. Transcriptomic analyses revealed the upregulation of genes involved in melanosome formation, melanin synthesis, lipid metabolism, and carotenoid accumulation. These findings demonstrate that, in addition to controlling steroidogenesis, mc2r plays a key role in pigment cell development and metabolic regulation.

The online version contains supplementary material available at 10.1038/s41598-026-37998-7.