PUBLICATION

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

Authors

Decker, A.R., McNeill, M.S., Lambert, A.M., Overton, J.D., Chen, Y.C., Lorca, R.A., Johnson, N.A., Brockerhoff, S.E., Mohapatra, D.P., Macarthur, H., Panula, P., Masino, M.A., Runnels, L.W., and Cornell, R.A.

ID

ZDB-PUB-140123-3

Date

2014

Source

Developmental Biology 386(2): 428-39 (Journal)

Registered Authors

Brockerhoff, Susan, Chen, Yu-Chia, Cornell, Robert, Panula, Pertti

Keywords

Dopamine, Parkinson's, TRPM7, Zebrafish

MeSH Terms

Analysis of Variance
Zebrafish/genetics
Zebrafish/growth & development*
Deferoxamine/pharmacology
Animals
Melanocytes/metabolism
TRPM Cation Channels/genetics*
Tyrosine 3-Monooxygenase/metabolism
Dopaminergic Neurons/cytology*
Cell Differentiation/physiology*
Patch-Clamp Techniques
Reverse Transcriptase Polymerase Chain Reaction
Mutation/genetics
Zebrafish Proteins/genetics*
Electroretinography
DNA Primers/genetics
Larva/growth & development
Cell Line
Motor Activity/drug effects
Motor Activity/genetics*
Motor Activity/physiology
Protein Serine-Threonine Kinases/genetics*
1-Methyl-4-phenylpyridinium/toxicity

(all 23)

PubMed

24291744 Full text @ Dev. Biol.

CTD

24291744

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.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
trpm7^b508/b508	standard conditions	Day 5	whole organism	RTPCR	Fig. 5
WT	standard conditions	Day 5	whole organism	RTPCR	Fig. 5
ot80Tg	standard conditions	Day 5	pretectum	IFL	Fig. 5
trpm7^b508/b508; ot80Tg	standard conditions	Day 5	pretectum	IFL	Fig. 5
ot80Tg	standard conditions	Day 5	hypothalamus	IHC	Fig. 5
trpm7^b508/b508	standard conditions	Day 5	whole organism	RTPCR	Fig. 5
trpm7^b508/b508; ot80Tg	standard conditions	Day 5	hypothalamus	IHC	Fig. 5
WT	standard conditions	Day 5	whole organism	RTPCR	Fig. 5
trpm7^b508/b508	chemical treatment: pharmaceutical	Day 5	hypothalamus	ISH	Fig. 4
trpm7^b508/b508	standard conditions	Day 5	hypothalamus	ISH	Fig. 4

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
ot80Tg	standard conditions	Day 5	pretectum serotonergic neuron increased amount, abnormal	Fig. 5
trpm7^b508/b508	control	Day 5	swimming behavior duration, abnormal	Fig. 3
trpm7^b508/b508	standard conditions	Prim-15	melanocyte regulation of membrane potential disrupted, abnormal	Fig. 1
trpm7^b508/b508	standard conditions	Day 5	dopaminergic neuron decreased amount, abnormal	Fig. 5
trpm7^b508/b508	standard conditions	Day 5	pretectum serotonergic neuron normal amount, normal	Fig. 5
trpm7^b508/b508	standard conditions	Day 5	swimming behavior decreased process quality, abnormal	Fig. 6
trpm7^b508/b508	standard conditions	Day 5	swimming behavior duration, abnormal	Fig. 2
trpm7^b508/b508	chemical treatment: desferrioxamine B mesylate	Day 5	swimming behavior decreased process quality, abnormal	Fig. 6
trpm7^b508/b508	chemical treatment: drug	Day 5	swimming behavior duration, normal	Fig. 3
trpm7^b508/b508; ot80Tg	standard conditions	Day 5	pretectum serotonergic neuron increased amount, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
b508		Small Deletion	trpm7
ot80Tg	Tg(slc6a3:EGFP)	Transgenic Insertion
w2		Point Mutation	mitfa

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
mitfa^w2/w2
ot80Tg
trpm7^b508/b508
trpm7^b508/b508; ot80Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Decker et al., 2014 ZDB-PUB-140123-3 PMID:24291744

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

Decker et al., 2014

ZDB-PUB-140123-3
PMID:24291744