Cell death of melanophores in zebrafish trpm7 mutant embryos depends on melanin synthesis.
Transient receptor potential melastatin 7 (TRPM7) is a broadly expressed, non-selective cation channel. Studies in cultured cells implicate TRPM7 in regulation of cell growth, spreading, and survival. However, zebrafish trpm7 homozygous mutants display death of melanophores and temporary paralysis, but no gross morphological defects during embryonic stages. This phenotype implies that melanophores are unusually sensitive to decreases in Trpm7 levels, a hypothesis we investigate here. We find that pharmacological inhibition of caspases does not rescue melanophore viability in trpm7 mutants, implying that melanophores die by a mechanism other than apoptosis. Consistent with this possibility, ultrastructural analysis of dying melanophores in trpm7 mutants reveals abnormal melanosomes and evidence of a ruptured plasma membrane, indicating that cell death occurs by necrosis. Interestingly, inhibition of melanin synthesis largely prevents melanophore cell death in trpm7 mutants. These results suggest that melanophores require Trpm7 in order to detoxify intermediates of melanin synthesis. We find that unlike TRPM1, TRPM7 is expressed in human melanoma cell lines, indicating that these cells may also be sensitized to reduction of TRPM7 levels.
McNeill
Matthew S
MS
Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, USA.
Paulsen
Jennifer
J
Bonde
Gregory
G
Burnight
Erin
E
Hsu
Mei-Yu
MY
Cornell
Robert A
RA
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival; D004625:Embryo, Nonmammalian / Q000166:cytology; D008274:Magnesium / Q000494:pharmacology; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000737:chemistry; D008547:Melanophores / Q000166:cytology*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D050053:TRPM Cation Channels / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D061945:Caspase Inhibitors; D008543:Melanins; D050053:TRPM Cation Channels; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D019009:Proto-Oncogene Proteins c-kit; D017346:Protein Serine-Threonine Kinases; C501875:Trpm7 protein, zebrafish; D008274:Magnesium