Absence of MBP 3' UTR in Mice Disrupts mRNA Transport, Myelination, and Motor Learning

Myelin sheath maturation requires compaction, a cellular phenomenon mediated by local translation of myelin basic protein (MBP), which acts as a molecular zipper to join adjacent membranes and extrude the cytoplasm. Contrary to decades-old microinjection experiments indicating that Mbp mRNA transport is restricted to microtubules, we now show using smFISH that endogenous Mbp mRNA granules indeed localize along actin. To validate the in vivo necessity of Mbp mRNA transport and its dependence on the 3 UTR (untranslated region), we replaced the endogenous Mbp 3 UTR with polyA tail sequences. Though these mice have decreased Mbp mRNA levels, this alone could not account for their striking phenotypes - hypomyelination, baseline tremors, and motor learning defects. Thus, we cultured oligodendrocytes from these mice and found defects in both Mbp mRNA localization and local translation. These results demonstrate that the 3 UTR of a locally translated structural protein is critical for both developmental and activity-induced myelination.