title: Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern.
abstract: Transient receptor potential, melastatin-like 7 (Trpm7) is a combined ion channel and kinase implicated in the differentiation or function of many cell types. Early lethality in mice and frogs depleted of the corresponding gene impedes investigation of the functions of this protein particularly during later stages of development. By contrast, zebrafish trpm7 mutant larvae undergo early morphogenesis normally and thus do not have this limitation. The mutant larvae are characterized by multiple defects including melanocyte cell death, transient paralysis, and an ion imbalance that leads to the development of kidney stones. Here we report a requirement for Trpm7 in differentiation or function of dopaminergic neurons in vivo. First, trpm7 mutant larvae are hypomotile and fail to make a dopamine-dependent developmental transition in swim-bout length. Both of these deficits are partially rescued by the application of levodopa or dopamine. Second, histological analysis reveals that in trpm7 mutants a significant fraction of dopaminergic neurons lack expression of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Third, trpm7 mutants are unusually sensitive to the neurotoxin 1-methyl-4-phenylpyridinium, an oxidative stressor, and their motility is partially rescued by application of the iron chelator deferoxamine, an anti-oxidant. Finally, in SH-SY5Y cells, which model aspects of human dopaminergic neurons, forced expression of a channel-dead variant of TRPM7 causes cell death. In summary, a forward genetic screen in zebrafish has revealed that both melanocytes and dopaminergic neurons depend on the ion channel Trpm7. The mechanistic underpinning of this dependence requires further investigation.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Decker
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: McNeill
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Lambert
authors.affiliation: UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Overton
authors.affiliation: Neuroscience Center and Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland.
authors.forename: Yu-Chia
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, IA 52245, United States.
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Lorca
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Johnson
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Brockerhoff
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, IA 52245, United States.
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
authors.affiliation: Department of Pharmacological and Physiological Science, St. Louis University, St. Louis, MO 63104, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: MacArthur
authors.affiliation: Neuroscience Center and Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland.
authors.forename: Pertti
authors.initials: P
authors.lastname: Panula
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Masino
authors.affiliation: UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: Loren W
authors.initials: LW
authors.lastname: Runnels
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, United States; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, United States. Electronic address: robert-cornell@uiowa.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cornell
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000166:cytology*; D004596:Electroretinography; D007814:Larva / Q000254:growth & development; D008544:Melanocytes / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development*; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D017931:DNA Primers; D050053:TRPM Cation Channels; D029961:Zebrafish Proteins; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; C501875:Trpm7 protein, zebrafish; D003676:Deferoxamine; D015655:1-Methyl-4-phenylpyridinium
keywords: Dopamine; Parkinson's; TRPM7; Zebrafish