ZFIN ID: ZDB-PUB-180324-12
Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology
Perez, D.E., Henle, A.M., Amsterdam, A., Hagen, H.R., Lees, J.A.
Date: 2018
Source: Pigment cell & melanoma research   31(5): 604-613 (Journal)
Registered Authors: Amsterdam, Adam, Henle, Andrea, Lees, Jaqueline, Perez, Dahlia
Keywords: GNAQ, GNA11, melanocyte, melanophore, uveal melanoma, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified/genetics
  • Animals, Genetically Modified/growth & development
  • Cells, Cultured
  • GTP-Binding Protein alpha Subunits/genetics*
  • GTP-Binding Protein alpha Subunits, Gq-G11/genetics*
  • Humans
  • Hyperpigmentation/genetics
  • Hyperpigmentation/pathology*
  • Melanocytes/metabolism
  • Melanocytes/pathology*
  • Melanoma/genetics
  • Melanoma/pathology*
  • Mutation*
  • Precancerous Conditions/genetics
  • Precancerous Conditions/pathology*
  • Uveal Neoplasms/genetics
  • Uveal Neoplasms/pathology*
  • Zebrafish/genetics
  • Zebrafish/growth & development
PubMed: 29570931 Full text @ Pigment Cell Melanoma Res.
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ABSTRACT
Uveal melanoma (UM) is the most common primary intraocular cancer and has a high incidence of metastasis, which lacks any effective treatment. Here, we present zebrafish models of UM, which are driven by melanocyte-specific expression of activating GNAQ or GNA11 alleles, GNAQ/11Q209L , the predominant initiating mutations for human UM. When combined with mutant tp53, GNAQ/11Q209L transgenics develop various melanocytic tumors, including UM, with near complete penetrance. These tumors display nuclear YAP localization and thus phenocopy human UM. We show that GNAQ/11Q209L expression induces profound melanocyte defects independent of tp53 mutation, which are apparent within 3 days of development. First, increases in melanocyte number, melanin content, and subcellular melanin distribution result in hyperpigmentation. Additionally, altered melanocyte migration, survival properties, and evasion of normal boundary cues lead to aberrant melanocyte localization and stripe patterning. Collectively, these data show that GNAQ/11Q209L is sufficient to induce numerous protumorigenic changes within melanocytes.
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