Dynamic CCN3 expression in the murine CNS does not confer essential roles in myelination or remyelination

Rosana Penalva,Alerie G. de la Fuente,José R. Hombrebueno,Bernard Perbal,Nira de la Vega Gallardo,John Falconer,Marie Dittmer,Michelle Naughton,Emma Evergren,Denise C. Fitzgerald,Jill Moffat,Rebecca J. Ingram,Zhiyong Lin

doi:10.1073/pnas.1922089117

Abstract

CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3-/- mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.

Highlights

communication network factor 3 (CCN3) is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo
We provide a comprehensive characterization of CCN3 protein expression in the adult, healthy murine central nervous system (CNS)
We show that CCN3 was transiently up-regulated during CNS demyelination and remyelination but is not necessary for efficient oligodendrocyte progenitor cell (OPC) differentiation during myelin regeneration

Summary

Introduction

CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3−/− mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo. There are currently no therapies targeting myelin regeneration, but proof-of-concept studies and clinical trials have shown that enhancing remyelination can improve neurological function [7, 8] These reports show value in studying mechanisms that may regulate oligodendrocyte progenitor cell (OPC) differentiation and remyelination. Overexpressing CCN3 in mouse cerebral cortex at E14 inhibited callosal projections during development [18] These reports suggest that CCN3 plays a role in murine CNS development, but, in general, functions of CCN3 in the CNS remain poorly characterized.

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Conclusion