PPAR delta agonists stimulate oligodendrocyte differentiation in tissue culture

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated tr anscription factors of the nuclear hormone receptor superfamily that have b een described as master genes that switch cells from an undifferentiated ph enotype to a differentiated phenotype. In the present investigation, we exa mined the possibility that ligands for PPARs are potent activators of oligo dendrocyte (OL) differentiation and/or proliferation. Primary glial culture s and enriched OL cultures of neonatal mouse cerebra were treated with thre e different PPAR agonists: a PPAR gamma -selective agonist, a PPAR delta -s elective agonist, and a pan agonist selective for both PPAR gamma and delta . Treatment with PPAR gamma agonist does not have an effect on the differen tiation of OLs; however, PPAR delta agonist and the pan agonist treatment a ccelerates the differentiation of OLs within 24 h of application in mixed g lial cultures. The number of OLs with processes and huge membrane sheets in creases two- to threefold in both groups. The increase in the size of the s heets is also mirrored by changes in the intensity and distribution of myel in basic protein (MBP) and proteolipid protein (PLP) mRNAs. As compared to controls, the PPAR delta agonist-treated groups contain more OLs that have MBP and PLP mRNA extending into distal processes. These results indicate th at PPAR delta plays a significant role in the maturation of OLs and regulat es the size of OL sheets. BrdU immunostaining reveals that these agonists d o not significantly stimulate proliferation of OLs expressing glycolipids. The studies in enriched OL cultures reproduce the effects of the PPAR agoni sts seen in the mixed glial cultures, indicating that the effect of the PPA R agonists is directly on the OLs and not via astrocytes. In the enriched c ultures, the total number of OLs increases significantly in the PPAR delta agonist-treated groups, but BrdU immunostaining does not show an increased proliferation of cells. These findings suggest that PPAR delta increases th e survival of cells and/or prevents cell death in enriched cultures. Althou gh PPAR delta is expressed in various cell types, its role as a factor in t he transcriptional regulation of OL differentiation has not been explored. We show for the first time that a ligand that serves as an agonist for PPAR delta activates the program of OL differentiation in primary and enriched OL cultures. (C) 2001 Wiley-Liss, Inc.