Oligodendrocyte progenitor cells (OPCs) comprise the largest proliferating cell population in the adult brain and dysregulated OPC proliferation has been associated with the formation of pediatric and adult gliomas. The purpose of this research is to determine whether non-clustered protocadherins regulate OPC proliferation by influencing their homeostatic self-renewal and homotypic self-repulsion in the central nervous system (CNS), and whether the dysregulation of non-clustered protocadherin signaling on OPCs can initiate glioma formation. Protocadherin 15 (PCDH15) is a member of the cadherin superfamily of transmembrane proteins that mediate calcium-dependent cell adhesion. Microarray and RNA sequencing data indicate that Pcdh15 mRNA is highly expressed by OPCs in the healthy developing mouse cortex and its expression within gliomas predict tumor aggression. By performing immunohistochemistry, we found that OPCs and oligodendrocytes express Pcdh15 in vitro and in vivo. Furthermore, the shRNA-mediated knockdown of Pcdh15 triggered a significant increase in OPC proliferation that was dependent on the increased activation of extracellular signal-related kinase (ERK). However, reducing Pcdh15 expression also reduced the number of processes produced by OPCs and the frequency with which they extruded and retracted lamellipodia (increased veiling time). Pcdh15 knockdown also altered contact-mediated interactions between adjacent OPCs, with the filopodia of adjacent Pcdh15 knockdown OPCs contacting for longer without pulling away. Unlike OPC proliferation, these changes were not affected by ERK activation, but were the result of altered Cdc42-Arp2/3 activation.