Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination

This proposal focuses on addressing one of the most fundamental questions regarding OL biology: What
axonal cues in the CNS microenvironment control OL differentiation and myelination? While it is still yet
unclear whether the spatial and temporal patterns of myelination are dependent on inductive or inhibitory cues
(or both), we know that exclusively axons – but not all axons – are myelinated by OLs in parallel with neuronal
circuit maturation. This suggests that axon-derived signals must be involved in coordinating this process. In
this proposal, we have identified a novel axon-derived peptide class, namely dynorphins that promote OL
differentiation and myelination. Neuropeptides, have several characteristics that make them an ideal axonal
signal to regulate myelination. They are stored in dense core vesicles and released only in response to high
levels of neuronal activity, a phenomenon that might signal a form of maturation that qualifies an axon for
myelination. Neuropeptides bind to G-protein coupled receptors and have slow-acting effects that may include
altering gene expression, providing a mechanism through which they might alter cellular fate. In this proposal
we will investigate: 1. Whether OLs and their precursors are influenced by the neuropeptide class, dynorphin,
2. Whether dynorphins are released in response to neuronal activity to regulate myelination and 3. Whether
dynorphins influence myelination globally or is restricted only to dynorphin expressing axons. Recent studies
demonstrate that biophysical properties of fiber diameter, inhibitory molecules and neuronal activity may all
affect OL precursor cell (OPC) proliferation, differentiation, and the selection of axons for myelination (Gibson
et al., 2014; Hines et al., 2015; Mensch et al., 2015; Redmond et al., 2016; Mitew et al., 2018; Mayoral et al.,
2018). Here, we provide the molecular mechanism and downstream signaling pathways for a specific
subset of neurons that may underlie activity dependent differentiation and myelination. Our preliminary
data place us in a unique position to determine whether dynorphins are a neuropeptide class that represents
an axonal cue to control OL differentiation and myelination. We believe that these findings should impart
valuable insight in providing a framework for identifying additional neuropeptides and transmitters that may
influence oligodendroglial lineage cells, as well as for profiling inhibitory and inductive cues for myelination.

Grant Number: 5R01NS115746-05
NIH Institute/Center: NIH
Principal Investigator: Jonah Chan