title: Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ).
abstract: Retinoic acid (RA) regulates gene transcription by activating the nuclear receptors retinoic acid receptor (RAR) and peroxisome proliferator-activated receptor (PPAR) β/δ and their respective cognate lipid-binding proteins CRABP-II and FABP5. RA induces neuronal differentiation, but the contributions of the two transcriptional pathways of the hormone to the process are unknown. Here, we show that the RA-induced commitment of P19 stem cells to neuronal progenitors is mediated by the CRABP-II/RAR path and that the FABP5/PPARβ/δ path can inhibit the process through induction of the RAR repressors SIRT1 and Ajuba. In contrast with its inhibitory activity in the early steps of neurogenesis, the FABP5/PPARβ/δ path promotes differentiation of neuronal progenitors to mature neurons, an activity mediated in part by the PPARβ/δ target gene PDK1. Hence, RA-induced neuronal differentiation is mediated through RAR in the early stages and through PPARβ/δ in the late stages of the process. The switch in RA signaling is accomplished by a transient up-regulation of RARβ concomitantly with a transient increase in the CRABP-II/FABP5 ratio at early stages of differentiation. In accordance with these conclusions, hippocampi of FABP5-null mice display excess accumulation of neuronal progenitor cells and a deficit in mature neurons versus wild-type animals.
authors.affiliation: Department of Pharmacology, Western Reserve University School of Medicine,Cleveland, Ohio 44106, USA.
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Yu
authors.forename: Liraz
authors.initials: L
authors.lastname: Levi
authors.forename: Ruth
authors.initials: R
authors.lastname: Siegel
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D060588:LIM Domain Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D048068:PPAR-beta; C000631433:Pdk1 protein, mouse; C091778:Ppard protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; C485607:ajuba protein, mouse; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1