G protein-coupled receptor GPR37-like 1 regulates adult oligodendrocyte generation.

Oligodendrocytes (OLs) continue to be generated from OL precursors (OPs) in the adult mammalian brain. Adult-born OLs are believed to contribute to neural plasticity, learning and memory through a process of "adaptive myelination," but how adult OL generation and adaptive myelination are regulated remains unclear. Here, we report that the glia-specific G protein-coupled receptor 37-like 1 (GPR37L1) is expressed in subsets of OPs and newly formed immature OLs in adult mouse brain. We found that OP proliferation and differentiation are inhibited in the corpus callosum of adult Gpr37l1 knockout mice, leading to a reduction in the number of adult-born OLs. Our data raise the possibility that GPR37L1 is mechanistically involved in adult OL generation and adaptive myelination, and suggest that GPR37L1 might be a useful functional marker of OPs that are committed to OL differentiation.

Characterization of a long noncoding RNA Pcdh17it as a novel marker for immature premyelinating oligodendrocytes.

Oligodendrocyte precursors (OPs) proliferate and differentiate into oligodendrocytes (OLs) during postnatal development and into adulthood in the central nervous system (CNS). Following the initiation of differentiation, OPs give rise to immature, premyelinating OLs, which undergo further differentiation and mature into myelin-forming OLs. We identified an immature OL-specific long noncoding RNA, named Pcdh17it. Through co-localization analysis and morphological characterization of OLs, we found that Pcdh17it is a specific marker for newly born immature OLs in the developing and adult forebrain of mice, and we used this new marker to analyze OL generation over the lifespan of mice. Pcdh17it is an effective tool for monitoring newly born OLs in adult brain, allowing detailed study of the dynamics of OP differentiation into OLs in the normal and pathological CNS.

Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning.

We identified mRNA encoding the ecto-enzyme Enpp6 as a marker of newly forming oligodendrocytes, and used Enpp6 in situ hybridization to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Within just 2.5 h of exposure to the complex wheel, production of Enpp6-expressing immature oligodendrocytes was accelerated in subcortical white matter; within 4 h, it was accelerated in motor cortex. Conditional deletion of myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6(+) oligodendrocytes and impaired learning within the same ∼2-3 h time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We concluded that new oligodendrocytes contribute to both early and late stages of motor skill learning.