Attractin/Mahogany/Zitter plays a critical role in myelination of the central nervous system

Abstract

The rat zitter (zi) mutation induces hypomyelination and vacuolation in the central nervous system (CNS), which result in early-onset tremor and progressive flaccid paresis. By positional cloning, we found a marked decrease in Attractin (Atrn) mRNA in the brain of the zi͞zi rat and identified zi as an 8-bp deletion at a splice donor site of Atrn. Atrn has been known to play multiple roles in regulating physiological processes that are involved in monocyte-T cell interaction, agouti-related hair pigmentation, and control of energy homeostasis. Rat Atrn gene encoded two isoforms, a secreted and a membrane form, as a result of alternative splicing. The zi mutation at the Atrn locus darkened coat color when introduced into agouti rats, as also described in mahogany (mg) mice, carrying the homozygous mutation at the Atrn locus. Transgenic rescue experiments showed that the membrane-type Atrn complemented both neurological alteration and abnormal pigmentation in zi͞zi rats, but that the secreted-type Atrn complemented neither mutant phenotype. Furthermore, we discovered that mg mice exhibited hypomyelination and vacuolation in the CNS associated with body tremor. We conclude from these results that the membrane Atrn has a critical role in normal myelination in the CNS and would provide insights into the physiology of myelination as well as the etiology of myelin diseases. T he zitter rat was found in a colony of Sprague-Dawley rats as a tremorous mutant, and subsequent genetic analysis showed that the abnormality was caused by an autosomal recessive gene, zitter (zi) (1, 2). The tremor develops spontaneously at 3 weeks of age, and flaccid paresis of the hind limb is observed at around 6 months of age (3). The main pathological findings are progressive hypomyelination and vacuolation in the central nervous system (CNS) (4). Hypomyelination is characterized by a significant decrease in the density of myelinated fibers and the number of myelin lamellae and is accompanied by aberrant or elongated myelin sheath formation (4). Vacuoles consist mainly of swollen astrocytic processes and enlargement of extracellular space as well as periaxonal spaces. The vacuoles are first detected in the pons and the outer thalamus at 3 weeks of age. With increasing age, vacuoles extend into the deep cortex, hippocampus, cervical spinal gray matter, and the granular layer and white matter of the cerebellum (5). However, the initiation of myelination and the fundamental structures of myelin sheaths are normal in the zitter rat. The biochemical components of myelin, such as myelin basic protein, proteolipid protein, and myelin-associated glycoprotein, are also normally expressed (5, 6). Therefore, the zitter rat is expected to provide useful tools for the study of axon-glia interaction and the assembly of myelin sheaths in the complex process of CNS myelination.The zi gene has been mapped to a genomic region between IL-1␤ (Il1b) and prion protein (Prnp) on rat chromosome (Chr) 3q35 (3, 7). Prnp is known as a causative gene for spongiform ence...

Prions disturb post-Golgi trafficking of membrane proteins

“…We asked whether impaired post-Golgi vesicle transport could be relevant to the pathogenesis of prion diseases. Loss of attractin function was shown to cause prion disease-like spongiform changes in the brains of animals 22 . Therefore, we semi-quantified cell surface attractin in uninfected N2aC24, infected N2aC24L1-3 and cured N2aC24L1-3 cells, using biotin labelling of cell surface proteins.…”

“…Spongiform neurodegeneration is a pathological hallmark of prion diseases. Loss-of-function for attractin, a large transmembrane protein that is conserved among animals, is known to cause prion disease-like spongiform neurodegeneration 22 . Similar spongiform neurodegeneration is reported in mice lacking functional mahogunin, a cytosolic E3 ubiquitin ligase, suggesting that mahogunin is a downstream molecule of attractin 32 .…”

“…Loss-of-function for attractin causes prion disease-like spongiform neurodegeneration in animals 22 . However, the role of the insulin receptor (IR) and attractin in prion diseases is unknown.…”

Genetic Analyses of Fancy Rat-Derived Mutations

“…Genotyping was performed as described previously [16] with a set of highly informative simple sequence length polymorphism (SSLP) markers [20]. …”

Expression Quantitative Trait Loci Analysis of 13 Genes in the Rat Prostate

“…A differential gene expression could be due to a cis-acting polymorphism at the gene itself (Baier et al 2000;Kuramoto et al 2001) or due to a polymorphism of a gene upstream. Therefore, analysis of determinants of differential gene expression is important not only for studying the architecture of transcriptional regulation in vivo, but also for identifying causative genes for various phenotypes.…”