TY - JOUR
T1 - Disruption of actin-binding domain-containing dystonin protein causes dystonia musculorum in mice
AU - Horie, Masao
AU - Watanabe, Keisuke
AU - Bepari, Asim K.
AU - Nashimoto, Jun ichiro
AU - Araki, Kimi
AU - Sano, Hiromi
AU - Chiken, Satomi
AU - Nambu, Atsushi
AU - Ono, Katsuhiko
AU - Ikenaka, Kazuhiro
AU - Kakita, Akiyoshi
AU - Yamamura, Ken ichi
AU - Takebayashi, Hirohide
N1 - Publisher Copyright:
© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (DstGt) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl-β-D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel DstGt mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose DstGt allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype. The Dystonin gene is responsible for dystonia musculorum, an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. We generated novel multipurpose Dystonin gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dystonia musculorum phenotypes, which are also confirmed by the electromyogram analysis.
AB - The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (DstGt) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl-β-D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel DstGt mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose DstGt allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype. The Dystonin gene is responsible for dystonia musculorum, an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. We generated novel multipurpose Dystonin gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dystonia musculorum phenotypes, which are also confirmed by the electromyogram analysis.
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U2 - 10.1111/ejn.12711
DO - 10.1111/ejn.12711
M3 - Article
C2 - 25195653
AN - SCOPUS:84916894733
SN - 0953-816X
VL - 40
SP - 3458
EP - 3471
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 10
ER -