Attractin/mahogany/zitter plays a critical role in myelination of the central nervous system

Takashi Kuramoto, Kazuhiro Kitada, Toshihide Inui, Yoshifumi Sasaki, Kazumi Ito, Takao Hase, Saburo Kawagachi, Yoshihiro Ogawa, Kazuwa Nakao, Gregory S. Barsh, Minako Nagao, Toshikazu Ushijima, Tadao Serikawa

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

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 zi/zi 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 zi/zi 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.

Original languageEnglish
Pages (from-to)559-564
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number2
DOIs
Publication statusPublished - Jan 16 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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