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

The rat titter (zi) mutation induces hypomyelination and vacuolation in the central nervous system (CNS), which result in early-onset tremor and progr essive flaccid paresis. By positional cloning, we found a marked decrease i n 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 pla y 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 th e Atrn locus darkened coat color when introduced into agouti rats, as also described in mahogany (mg) mice, carrying the homozygous mutation at the At rn locus. Transgenic rescue experiments showed that the membrane-type Atrn complemented both neurological alteration and abnormal pigmentation in zi/z i rats, but that the secreted-type Atrn complemented neither mutant phenoty pe. Furthermore, we discovered that mg mice exhibited hypomyelination and v acuolation in the CNS associated with body tremor. We conclude from these r esults that the membrane Atrn has a critical role in normal myelination in the CNS and would provide insights into the physiology of myelination as we ll as the etiology of myelin diseases.