Identifying in vivo genetic dependencies of melanocyte and melanoma development

Abstract The advent of large-scale sequencing in both development and disease has identified large numbers of candidate genes that may be linked to important phenotypes. We have developed a rapid, scalable system for assessing the role of candidate genes using zebrafish. We generated transgenic zebrafish in which Cas9 was knocked-in to the endogenous mitfa locus, a master transcription factor of the melanocyte lineage. The main advantage of this system compared to existing techniques is maintenance of endogenous regulatory elements. We used this system to identify both cell-autonomous and non-cell autonomous regulators of normal melanocyte development. We then applied this to the melanoma setting to demonstrate that loss of genes required for melanocyte survival can paradoxically promote more aggressive phenotypes, highlighting that in vitro screens can mask in vivo phenotypes. Our genetic approach offers a versatile tool for exploring developmental processes and disease mechanisms that can readily be applied to other cell lineages.

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Published
2025-07-18
DOI
https://doi.org/10.7554/elife.100257.2
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
0.00

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article

Identifying in vivo genetic dependencies of melanocyte and melanoma development

Miranda V. Hunter, Julia Xia, Maura McGrail, Sarah C. Perlee et al.
Single-cell and spatial transcriptomics
article

Identifying in vivo genetic dependencies of melanocyte and melanoma development

Miranda V. Hunter, Julia Xia, Maura McGrail, Sarah C. Perlee, Yilun Ma, Richard M. White, Nelly M. Cruz, Timothée Lionnet, Jacob B Swanson, Zhitao Ming
article en

Abstract

Abstract The advent of large-scale sequencing in both development and disease has identified large numbers of candidate genes that may be linked to important phenotypes. We have developed a rapid, scalable system for assessing the role of candidate genes using zebrafish. We generated transgenic zebrafish in which Cas9 was knocked-in to the endogenous mitfa locus, a master transcription factor of the melanocyte lineage. The main advantage of this system compared to existing techniques is maintenance of endogenous regulatory elements. We used this system to identify both cell-autonomous and non-cell autonomous regulators of normal melanocyte development. We then applied this to the melanoma setting to demonstrate that loss of genes required for melanocyte survival can paradoxically promote more aggressive phenotypes, highlighting that in vitro screens can mask in vivo phenotypes. Our genetic approach offers a versatile tool for exploring developmental processes and disease mechanisms that can readily be applied to other cell lineages.

Memorial Sloan Kettering Cancer Center (US), Iowa State University (US), Cornell University (US), Institute for Systems Biology (US), University of Oxford (GB), New York University (US)
Melanoma Research Alliance, Memorial Sloan-Kettering Cancer Center, Pershing Square Sohn Cancer Research Alliance, Mark Foundation For Cancer Research, Debra and Leon Black Family Foundation, National Institutes of Health, Weill Cornell Medical College, National Cancer Institute, Office of Research Infrastructure Programs, National Institutes of Health
Openalex Percentile: Top 82%
Single-cell and spatial transcriptomics
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