Retinoic Acid Induces Neurogenesis by Activating Both Retinoic Acid Receptors (RARs) and Peroxisome Proliferator-activated Receptor β/δ (PPARβ/δ)*

Background: RA regulates transcription through the CRABP-II/RAR and FABP5/PPARβ/δ pathways, but the contributions of these pathways to RA-induced neuronal differentiation are unknown. Results: RA signaling switches from CRABP-II/RAR to FABP5/PPARβ/δ during differentiation. The switch is controlled by transient up-regulation of RARβ and the CRABP-II/FABP5 ratio. Conclusion: Both RA pathways are employed during neuronal differentiation. Significance: The data contribute insights into RA-induced neurogenesis. 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.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-10-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M112.410381PMID 23105114PMCID PMC3516764
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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