Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice. (6th September 2014)

• Record Type: Journal Article
• Authors: Horie, Masao; Watanabe, Keisuke; Bepari, Asim K.; Nashimoto, Jun‐ichiro; Araki, Kimi; Sano, Hiromi; Chiken, Satomi; Nambu, Atsushi; Ono, Katsuhiko; Ikenaka, Kazuhiro; Kakita, Akiyoshi; Yamamura, Ken‐ichi; Takebayashi, Hirohide
• Is Part Of: European journal of neuroscience. Volume 40:Number 10(2014:Nov.)
• Page Start: 3458
• Page End: 3471
• Publication Date: 2014-09-06
• Subjects: Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.12711
• Languages: English
• ISSNs: 0953-816X

Abstract

<abstract abstract-type="main" id="ejn12711-abs-0001"> <title>Abstract</title> <p>The <italic>Dystonin</italic> gene (<italic>Dst</italic>) is responsible for <italic>dystonia musculorum</italic> (<italic>dt</italic>), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. <italic>Dst‐a</italic> 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 <italic>dt</italic>, 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 <italic>Dst</italic> isoforms, we generated novel multipurpose <italic>Dst</italic> gene trap mice, in which actin‐binding domain‐containing isoforms are disrupted. Homozygous mice showed typical <italic>dt</italic> phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (<italic>Dst</italic><sup><italic>Gt</italic></sup>) 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 <italic>Dystonin</italic> 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 <italic>dt</italic> phenotype. These novel <italic>Dst</italic><sup><italic>Gt</italic></sup> mice showed that a loss‐of‐function mutation in the actin‐binding domain‐containing <italic>Dystonin</italic> isoforms led to typical <italic>dt</italic> phenotypes. Furthermore, this novel multipurpose <italic>Dst</italic><sup><italic>Gt</italic></sup> allele offers a unique tool for analysing the causative neuronal networks involved in the <italic>dt</italic> phenotype.</p> </abstract>