Identification of a putative receptor for the myeloid cell-derived growth factor oncomodulin and its role in CNS and PNS regeneration

Abstract

Purpose : Although the optic nerve, like other mature CNS pathways, cannot regenerate when injured, this failure can be partially reversed by inducing sterile inflammation in the eye. Previous work from our lab showed that this phenomenon is mediated in large part by oncomodulin (Ocm), a 12 kDa Ca++-binding protein that is secreted by myeloid cells. Ocm also induces outgrowth from dorsal ganglion neurons (DRGs) and may play a role in the conditioning lesion effect, whereby injury to a peripheral nerve enhances the ability of DRG neurons to extend central and peripheral axons into spinal cord and sciatic nerve respectively. So we aim to identify the Ocm receptor (Ocm-R) and explore its role in CNS and PNS regeneration.

Methods : Biotinylation by antibody recognition (BAR) followed by mass spectrometry were used to identify Ocm-R candidates. Co-immunoprecipitation and Biacore studies were used to reveal the direct interaction between Ocm and Ocm-R. Ocm-R expression in RGCs and DRG neurons were manipulated by CRISPR-Cas9 and aav2/9-short hairpin RNA (shRNA) targeting Ocm-R respectively. Ocm-R expression in cell line was overexpressed by plasmid transfection.

Results : We now report the isolation of a likely Ocm receptor (Ocm-R). Knock-down of Ocm-R in RGCs leads to the loss of Ocm binding to RGCs and a substantial loss of inflammation-induced regeneration after optic nerve injury without affecting regeneration induced by other means (pten deletion in RGCs). Conversely, ectopic expression of Ocm-R in cells with low baseline expression results in high Ocm binding. Moreover, Ocm-R knockdown reduces conditioning lesion induced DRGs neurons’ central and peripheral axon regeneration.

Conclusions : Oncomodulin and its receptor enable the conditioning lesion induced CNS and PNS regeneration.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.