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Published on: December 28, 2021
Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor
Amanda R Decker1, Matthew S McNeill2, Aaron M Lambert3
1Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, United States.
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.
Insights
Zebrafish lacking the Trpm7 ion channel show defects in dopaminergic neuron development and function. This study highlights Trpm7
Area of Science:
- Neuroscience
- Ion Channel Biology
- Developmental Biology
Background:
- Transient receptor potential, melastatin-like 7 (Trpm7) is a bifunctional protein with both ion channel and kinase activity.
- Trpm7 plays a role in various cell types, but its function in later developmental stages is difficult to study in mammals due to early lethality.
- Zebrafish offer a model to study Trpm7 function in later development, as trpm7 mutant larvae survive early morphogenesis.
Purpose of the Study:
- To investigate the role of Trpm7 in the differentiation and function of dopaminergic neurons in vivo.
- To characterize the specific defects associated with Trpm7 loss in dopaminergic neurons.
- To explore potential mechanisms underlying Trpm7's role in neuronal health and function.
Main Methods:
- Utilized zebrafish trpm7 mutant larvae to study Trpm7 function.
- Assessed larval motility and swim-bout behavior.
- Administered levodopa, dopamine, and deferoxamine to evaluate rescue effects.
- Performed histological analysis to examine tyrosine hydroxylase expression in dopaminergic neurons.
- Used SH-SY5Y cells to model human dopaminergic neurons and assess TRPM7 variant effects.
Main Results:
- Trpm7 mutant zebrafish larvae exhibit hypomotility and impaired dopamine-dependent swim-bout behavior, partially rescued by levodopa or dopamine.
- A significant proportion of dopaminergic neurons in trpm7 mutants fail to express tyrosine hydroxylase.
- Mutant larvae show increased sensitivity to the neurotoxin MPP+, with partial rescue by the antioxidant deferoxamine.
- Forced expression of a channel-dead TRPM7 variant in SH-SY5Y cells leads to cell death.
Conclusions:
- Zebrafish forward genetics screen identifies Trpm7 as essential for dopaminergic neuron differentiation and function.
- Trpm7 is crucial for maintaining dopaminergic neuron integrity and function, potentially through regulating oxidative stress.
- Further research is needed to elucidate the precise mechanisms by which Trpm7 influences neuronal health and development.
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