Ror1 promotes PPARα-mediated fatty acid metabolism in astrocytes.

Abstract

Ror1 signaling regulates cell polarity, migration, proliferation, and differentiation during developmental morphogenesis, and plays an important role in regulating neurogenesis in the embryonic neocortices. However, the role of Ror1 signaling in the brains after birth remains largely unknown. Here, we found that expression levels of Ror1 in the mouse neocortices increase during the postnatal period, when astrocytes mature and start expressing GFAP. Indeed, Ror1 is highly expressed in cultured postmitotic mature astrocytes. RNA-Seq analysis revealed that Ror1 expressed in cultured astrocytes mediates upregulated expression of genes related to fatty acid (FA) metabolism, including the gene encoding carnitine palmitoyl-transferase 1a (Cpt1a), the rate-limiting enzyme of mitochondrial fatty acid β-oxidation (FAO). We also found that Ror1 promotes the degradation of lipid droplets (LDs) accumulated in the cytoplasm of cultured astrocytes after oleic acid loading, and that suppressed expression of Ror1 decreases the amount of FAs localized at mitochondria, intracellular ATP levels, and expression levels of peroxisome proliferator-activated receptor α (PPARα) target genes, including Cpt1a. Collectively, these findings indicate that Ror1 signaling promotes PPARα-mediated transcription of FA metabolism-related genes, thereby facilitating the availability of FAs derived from LDs for mitochondrial FAO in the mature astrocytes.