Peroxisome proliferator-activated receptor γ is a novel target of the nerve growth factor signaling pathway in PC12 cells

Abstract

Peroxisome proilferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is subject to considerable interest because of its role in adipocyte differentiation, metabolic control, and anti-inflammatory action. PPARγ research in brain cells is presently focused on glial PPARγ because of its potential as a pharmacological target in the treatment of neurodegenerative diseases with an inflammatory component. In neurons PPARγ function is far from clear, and PPARγ agonist-dependent and -independent effects on cell survival or differentiation have been reported. We used PC12 cells, widely used to study neuronal signaling, such as nerve growth factor (NGF)-induced differentiation and survival or epidermal growth factor-dependent cell proliferation to dissect the possible involvement of PPARγ in these pathways. We show that NGF but not epidermal growth factor increases the transcriptional activity of PPARγ, and modulates the expression of this transcription factor. Because NGF signals through the tyrosine kinase (TrkA) NGF receptor and/or the p75NTR receptor, we used rescue experiments with a PC12 cell mutant lacking TrkA to show that NGF-induced PPARγ activation is dependent on TrkA activation. Our results point out PPARγ as a novel target of the TrkA-mediated neuronal cell survival and differentiating pathway and suggest a potential new inflammatory-independent therapeutic approach for pharmacological intervention in neurological disorders. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.