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.
Data availability
The datasets generated and/or analysed during the current study are available in the NCBI’s Gene Expression Omnibus (GEO) repository, [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi and Accession Number: GSE292242] and are also available from the corresponding author upon reasonable request.
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Acknowledgements
The authors thank to Lucía Sanchez-Ruiloba from the Advanced Microscopy and Imaging Service at IIM-CSIC for their invaluable assistance and expertise in microscopy, and Ms. Susana Otero for maintenance of the experimental animals and assistance during sampling.
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Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research was funded by the MCIN/AEI/https://doi.org/10.13039/501100011033 grant number AGL2017-89648P, ERDF A way of making Europe” and by PID2021-1236511OB-100 to Josep Rotllant and PID2022-136288OB-C33 to José Miguel Cerda-Reverter. Elisa Barreiro-Docío was a recipient of a JAE-Intro-ICU programme fellowship from the Spanish National Research Council (CSIC).
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E.B.D. Writing-original draft, Visualization, Methodology, Formal analysis, Data curation. L.G.P. Writing-original draft, Methodology, Formal analysis, Data curation. P.S. Writing-original draft, Methodology and Experimentation. L.M.M. Writing-Review and Editing, Methodology and Experimentation. C.C.P. Methodology and Experimentation. M.V.A Methodology and Experimentation. J.A.V. Writing-Review and Editing. L.T. Writing-Review and Editing, Methodology and Experimentation. J.M.C.R. Writing-Review and Editing, Conceptualization, Funding acquisition. J.R. Writing-Review and Editing, Conceptualization, Methodology, Resources, Funding acquisition. All authors reviewed and approved the final version.
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Barreiro-Docío, E., Guerrero-Peña, L., Soni, P. et al. Loss-of-function mutations in the melanocortin-2-receptor (mc2r) lead to skin hyperpigmentation in teleost fish. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37998-7
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DOI: https://doi.org/10.1038/s41598-026-37998-7
