Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern

Amanda R. Decker, Matthew S. McNeill, Aaron M. Lambert, Jeffrey D. Overton, Yu Chia Chen, Ramón A. Lorca, Nicolas A. Johnson, Susan E. Brockerhoff, Durga P. Mohapatra, Heather MacArthur, Pertti Panula, Mark A Masino, Loren W. Runnels, Robert A. Cornell

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)428-439
Number of pages12
JournalDevelopmental Biology
Volume386
Issue number2
DOIs
StatePublished - Feb 15 2014

Bibliographical note

Funding Information:
We are grateful to Austin Keeler, Hayley Martin, Christine Roenitz, Melina Hale, and Jonathan Doorn for preliminary work on this project. We thank James Gambrell for statistical consultation and Alan Kay for useful discussions and for chelators. This work was supported by the following grants: NIEHS/NIH P30 ES05605 ( University of Iowa Environmental Health Sciences Research Center ) (seed grant to RAC), GM067841 (RAC), NSF IOS-1147221 (RAC), R01EY018814 (SEB), R01EY015165 (SEB), Core Grant P30EY001730 (UW), NS069898 (DPM), NS065054 (MAM), RO1GM080753 (LWR), Academy of Finland 116177 (PP), Sigrid Juselius Foundation (PP). Matthew McNeill's current address: Institute for Genomic Biology, 1206W. Gregory, RM 2401G, University of Illinois, Urbana, IL.

Keywords

  • Dopamine
  • Parkinson's
  • TRPM7
  • Zebrafish

Fingerprint

Dive into the research topics of 'Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern'. Together they form a unique fingerprint.

Cite this