DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release.

Hye Ryeong Lim,Jeong Woo Park,Dong Jun Kim,Unn Hwa Lee,Chae Ha Yang,Mai-Tram Vo,Sang Ryong Kim,Hyun Kim,Byung Ju Lee,Chang Man Ha,Hee Young Kim,Jeongah Kim,Kyungjin Kim,Seongsoo Lee,Jong Hyuk Yoon,Jun Yeon Lee,Esther Yang,Ki-Jeong Kim ,Hyung Jun Kim ,June Choi

doi:10.3390/ijms21010060

Abstract

Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.

Highlights

Dopamine is a major neurotransmitter and plays an important role in motor control, and its dysfunction in the dopamine (DA) neuron circuitry affects various neuronal disorders such as Parkinson’s disease (PD), schizophrenia, and depression [1,2,3]
To provide insight into the functional roles of Developmentally regulated GTP-binding protein 2 (DRG2) in mouse development, we report here, for the first time, that DRG2-deficient mice exhibit a significant growth delay and reduced body weight accompanied by defective osteogenesis and a short life span
In micro-computerized tomography (CT) analyses of DRG2-deficient mice, it was clearly identified that unossified areas were significantly increased in the skull and that bone formation was dramatically reduced in the appendicular skeleton

Summary

Introduction

Dopamine is a major neurotransmitter and plays an important role in motor control, and its dysfunction in the dopamine (DA) neuron circuitry affects various neuronal disorders such as Parkinson’s disease (PD), schizophrenia, and depression [1,2,3]. Dopamine neurons from the SN send long axons to the Str to control locomotor activity, and MTs participate in axonal secretory vesicle transport [6]. The Rac protein, a member of the subfamily of Rho-GTPases, interacts with MTs [8], stabilizes MTs [9], and participates in the regulation of dopaminergic cell death, neuronal polarization, vesicle trafficking, and axon growth through cytoskeletal organization [10,11,12]. DRG2 interacts with Rab on vesicular endosomes and is involved in the regulation of endosomal Rab activity and endosome trafficking [18]. Considering the involvement of Tau [20] and MTs [7] in neurodegenerative diseases, we predict that DRG2 may play an important role in the pathogenesis of neurodegenerative diseases

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Results

Conclusion