The VF rat with abnormal myelinogenesis has a mutation in Dopey1
Miyuu Tanaka1, Takeshi Izawa, Jyoji Yamate
1Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano, Osaka, 598-8531, Japan.
Abstract:
The vacuole formation (VF) rat is an autosomal recessive myelin mutant characterized by generalized tremor, hypomyelination, and periaxonal vacuole formation of the central nervous system (CNS). Here, we report the most likely causative gene for neurological disease in the VF rat and pursue its roles in the development and maintenance of the CNS myelin. We identified a nonsense mutation in the dopey family member 1 (Dopey1) located on rat chromosome 8. Expression level of Dopey1 mRNA was decreased and DOPEY1 protein was undetectable both in the white and gray matter of the spinal cords in the VF rats. Double immunohistochemistry demonstrated that DOPEY1 was mainly expressed in neurons and oligodendrocytes in the wild-type rats, whereas no positive cells were detected in the VF rats. We also demonstrated a marked reduction in myelin components both at mRNA and protein levels during myelinogenesis in the VF rats. In addition, proteolipid protein and myelin-associated glycoprotein accumulated in oligodendrocyte cell body, suggesting that Dopey1 is likely to be involved in the traffic of myelin components. Our results highlighted the importance of Dopey1 for the development and maintenance of the CNS myelin.
Insights
A mutation in the dopey family member 1 (Dopey1) gene causes vacuole formation (VF) disease in rats, affecting central nervous system (CNS) myelin development and maintenance. This highlights Dopey1
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- The vacuole formation (VF) rat exhibits autosomal recessive myelin mutations, leading to tremors, hypomyelination, and central nervous system (CNS) vacuolation.
- Understanding the genetic basis of VF disease is crucial for elucidating myelin development and maintenance mechanisms.
Purpose of the Study:
- To identify the causative gene for neurological disease in the VF rat.
- To investigate the role of the identified gene in CNS myelin development and maintenance.
Main Methods:
- Genetic analysis to identify mutations in VF rats.
- Quantitative real-time PCR to assess Dopey1 mRNA expression levels.
- Western blotting and immunohistochemistry to detect DOPEY1 protein expression and localization in wild-type and VF rat spinal cords.
- Analysis of myelin component expression during myelinogenesis in VF rats.
Main Results:
- A nonsense mutation in the dopey family member 1 (Dopey1) gene was identified as the likely cause of VF disease.
- Dopey1 mRNA and protein were significantly reduced or undetectable in VF rat spinal cords.
- DOPEY1 protein was localized to neurons and oligodendrocytes in wild-type rats but absent in VF rats.
- Myelin components were markedly reduced, and myelin proteins accumulated in oligodendrocyte cell bodies in VF rats, suggesting impaired myelin component trafficking.
Conclusions:
- Dopey1 is essential for the proper development and maintenance of CNS myelin.
- The findings implicate Dopey1 in the trafficking of myelin components within oligodendrocytes.
- This study underscores the critical role of Dopey1 in maintaining myelin integrity and function.
