Disruption of actin-binding domain-containing Dystonin protein causes dystonia musculorum in mice.

Abstract

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 (Dst(Gt) ) 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 Dst(Gt) 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 Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.

• Authors: Masao Horie, Keisuke Watanabe, Asim K Bepari, Jun-Ichiro Nashimoto, Kimi Araki, Hiromi Sano, Satomi Chiken, Atsushi Nambu, Katsuhiko Ono, Kazuhiro Ikenaka, Akiyoshi Kakita, Ken-Ichi Yamamura, Hirohide Takebayashi
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 40 Issue 10 Pg. 3458-71 (Nov 2014) ISSN: 1460-9568 [Electronic] France
• PMID: 25195653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chemical References

• Carrier Proteins
• Cytoskeletal Proteins
• Dst protein, mouse
• Dystonin
• Nerve Tissue Proteins
• Protein Isoforms

Topics

• Animals
• Brain (pathology, physiopathology)
• Carrier Proteins (genetics, metabolism)
• Cytoskeletal Proteins (genetics, metabolism)
• Disease Models, Animal
• Dystonic Disorders (genetics, pathology, physiopathology)
• Dystonin
• Female
• Ganglia, Spinal (pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Muscle, Skeletal (physiopathology)
• Nerve Tissue Proteins (genetics, metabolism)
• Phenotype
• Protein Isoforms
• Spinal Cord (pathology, physiopathology)
• Trigeminal Nerve (pathology, physiopathology)