Regulation of zebrafish melanocyte development by ligand-dependent BMP signaling

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Abstract

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends on mitfa, an ortholog of MITF, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development.

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All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and supplements.

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Alec K Gramann

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Arvind M Venkatesan

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Melissa Guerin

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Craig J Ceol

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

For correspondence
craig.ceol@umassmed.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7188-7580

Funding

Melanoma Research Foundation

Alec K Gramann

National Cancer Institute (1F31CA239478-01)

Alec K Gramann

National Center for Advancing Translational Sciences (UL1-TR001453)

Alec K Gramann

Congressionally Directed Medical Research Programs (W8IXWH-13-0107)

Craig J Ceol

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063850)

Craig J Ceol

Sidney Kimmel Foundation for Cancer Research (SKF-13-123)

Craig J Ceol

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Zebrafish were handled in accordance with protocols approved by the University of Massachusetts Medical School IACUC protocol (A-2171-19). For procedures, including imaging and genotyping, animals were anesthetized in 0.17% tricaine or euthanized by overdose of tricaine. Every effort was made to minimize suffering.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.