PUBLICATION

Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish

Authors

Kalyn, M., Garvey, R., Lee, H., Mbesha, H.A., Curry, J., Saxena, V., Mennigen, J.A., Ekker, M.

ID

ZDB-PUB-241014-1

Date

2024

Source

Journal of neurochemistry : (Journal)

Registered Authors

Ekker, Marc, Mennigen, Jan, Saxena, Vishal

Keywords

dopamine, dopaminergic neurons, locomotion, metabolism, neurodegeneration, zebrafish

MeSH Terms

Zebrafish*
Behavior, Animal/physiology
Animals
Dopaminergic Neurons/metabolism
Nuclear Receptor Subfamily 4, Group A, Member 2*/genetics
Nuclear Receptor Subfamily 4, Group A, Member 2*/metabolism
Brain*/metabolism
Zebrafish Proteins*/genetics
Zebrafish Proteins*/metabolism
Animals, Genetically Modified

(all 10)

PubMed

39388214 Full text @ J. Neurochem.

Abstract

Dopaminergic (DAnergic) dysfunction and imbalanced dopamine (DA) levels are known contributors to the pathogenesis of numerous psychiatric and neurodegenerative disorders. Of the many identified risk factors for DA-associated disorders, nuclear receptor subfamily 4 group A2 (NR4A2; or nuclear receptor related-1 protein (NURR1)), a transcription factor involved in DAnergic differentiation, has been associated with Parkinson's disease and attention deficit hyperactive disorder (ADHD). In zebrafish, transient loss of nr4a2 was previously shown to decrease tyrosine hydroxylase (TH) expression and impair locomotion. To further characterize the roles of the two zebrafish nr4a2 paralogs, nr4a2a, and nr4a2b, we produced targeted loss-of-function mutants and examined DAnergic neuron regeneration, oxidative respiration, and behavioral traits. The loss of nr4a2a function more closely recapitulated Parkinsonian phenotypes and affected neurotrophic factor gene expression. Conversely, nr4a2b mutants displayed behavioral symptoms reminiscent of mice deficient in Nr4a2 with increased neurotrophic output. In contrast, nr4a2b mutants also displayed increased metabolic input from non-mitochondrial sources indicative of high cytosolic reactive oxygen species and perturbed mitochondrial function. The nr4a2a mutants also showed increased maximal respiration, which may suggest a compensatory mechanism to meet the metabolic requirements of DAnergic neuron health. Overall, the zebrafish mutants generated in this study helped uncover molecular mechanisms involved in DA-related disease pathologies, and in the regeneration of DAnergic neurons.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 7-13	whole organism nes expression increased amount, abnormal	Fig. 3
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 7-13	whole organism notch1a expression increased amount, abnormal	Fig. 3
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 7-13	whole organism shha expression decreased amount, abnormal	Fig. 3
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 7-13	whole organism th expression decreased amount, abnormal	Fig. 3
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 7-13	whole organism th expression increased amount, abnormal	Fig. 3
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 7-13 to Days 14-20	whole organism swimming decreased linear velocity, abnormal	Fig. 3
WT	chemical treatment by environment: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine	Days 14-20	whole organism th expression increased amount, abnormal	Fig. 3
nr4a2a^ot511/ot511	standard conditions	Adult	aerobic respiration increased occurrence, abnormal	Fig. 4
nr4a2a^ot511/ot511	standard conditions	Adult	brain bdnf expression decreased amount, abnormal	Fig. 4
nr4a2a^ot511/ot511	standard conditions	Adult	brain gdnfa expression decreased amount, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ot80Tg	Tg(slc6a3:EGFP)	Transgenic Insertion
ot511		Indel	nr4a2a
ot512		Small Deletion	nr4a2b

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
nr4a2a	CRISPR1-nr4a2a	CRISPR
nr4a2a	CRISPR2-nr4a2a	CRISPR
nr4a2a	CRISPR3-nr4a2a	CRISPR
nr4a2a	CRISPR4-nr4a2a	CRISPR
nr4a2b	CRISPR2-nr4a2b	CRISPR
nr4a2b	CRISPR3-nr4a2b	CRISPR
nr4a2b	CRISPR4-nr4a2b	CRISPR
nr4a2b	CRISPR5-nr4a2b	CRISPR

1 - 8 of 8

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Fish

Fish
nr4a2a^ot511/ot511
nr4a2a^ot511/ot511; ot80Tg
nr4a2b^ot512/ot512
nr4a2b^ot512/ot512; nr4a2a^ot511/ot511; ot80Tg
nr4a2b^ot512/ot512; ot80Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Kalyn et al., 2024 ZDB-PUB-241014-1 PMID:39388214

Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish

Kalyn et al., 2024

ZDB-PUB-241014-1
PMID:39388214