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.

[1]  S. Mandrup,et al.  The Orphan Nuclear Receptor Rev-Erbα Is a Peroxisome Proliferator-activated Receptor (PPAR) γ Target Gene and Promotes PPARγ-induced Adipocyte Differentiation* , 2003, Journal of Biological Chemistry.

[2]  I. Saluja,et al.  PPAR δ agonists stimulate oligodendrocyte differentiation in tissue culture , 2001 .

[3]  B. Desvergne,et al.  Peroxisome Proliferator-Activated Receptor β/δ in the Brain: Facts and Hypothesis , 2008, PPAR research.

[4]  L. Gudas,et al.  The level of CRABP-I expression influences the amounts and types of all-trans-retinoic acid metabolites in F9 teratocarcinoma stem cells. , 1992, The Journal of biological chemistry.

[5]  M. McBurney,et al.  P19 embryonal carcinoma cells. , 1993, The International journal of developmental biology.

[6]  H. T. Kang,et al.  Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells , 2009, Nucleic acids research.

[7]  N. Noy,et al.  Repression of Cellular Retinoic Acid-binding Protein II during Adipocyte Differentiation* , 2010, The Journal of Biological Chemistry.

[8]  H. Okano,et al.  Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1 , 2009, Proceedings of the National Academy of Sciences.

[9]  L. Lau,et al.  Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. Godbout,et al.  Fatty acid binding proteins in brain development and disease. , 2010, The International journal of developmental biology.

[11]  D. Levinthal,et al.  Distinct Roles for Cellular Retinoic Acid-binding Proteins I and II in Regulating Signaling by Retinoic Acid* , 1999, The Journal of Biological Chemistry.

[12]  Peng Liu,et al.  Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription , 2002, Molecular and Cellular Biology.

[13]  W. Wahli,et al.  Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway. , 2002, Molecular cell.

[14]  T. Schug,et al.  Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARβ/δ to RAR , 2008, Proceedings of the National Academy of Sciences.

[15]  Wade R. Smith,et al.  Peroxisome Proliferator-Activated Receptors: “Key” Regulators of Neuroinflammation after Traumatic Brain Injury , 2008, PPAR research.

[16]  T. Willson,et al.  Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ Stimulates Differentiation and Lipid Accumulation in Keratinocytes , 2004 .

[17]  Anthony J. Muslin,et al.  Ajuba, a Novel LIM Protein, Interacts with Grb2, Augments Mitogen-Activated Protein Kinase Activity in Fibroblasts, and Promotes Meiotic Maturation of Xenopus Oocytes in a Grb2- and Ras-Dependent Manner , 1999, Molecular and Cellular Biology.

[18]  A. Zelent,et al.  LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling , 2010, Proceedings of the National Academy of Sciences.

[19]  T. Yamashima,et al.  Differential expression of FABP 3, 5, 7 in infantile and adult monkey cerebellum , 2010, Neuroscience Research.

[20]  T. Schug,et al.  Opposing Effects of Retinoic Acid on Cell Growth Result from Alternate Activation of Two Different Nuclear Receptors , 2007, Cell.

[21]  J. Thompson,et al.  Transcriptional regulation of the cellular retinoic acid binding protein I gene in F9 teratocarcinoma cells. , 2000, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[22]  N. Noy,et al.  Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity , 2012, Diabetes.

[23]  M. Sakharkar,et al.  Computational identification and experimental validation of PPRE motifs in NHE1 and MnSOD genes of Human , 2009, BMC Genomics.

[24]  M. Maden.  Retinoic acid in the development, regeneration and maintenance of the nervous system , 2007, Nature Reviews Neuroscience.

[25]  M. McBurney,et al.  Control of muscle and neuronal differentiation in a cultured embryonal carcinoma cell line , 1982, Nature.

[26]  M. McBurney,et al.  Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells , 1982, The Journal of cell biology.

[27]  M. Endo,et al.  Cdc42-mTOR Signaling Pathway Controls Hes5 and Pax6 Expression in Retinoic Acid-dependent Neural Differentiation* , 2009, Journal of Biological Chemistry.

[28]  A. Kumar,et al.  Peroxisome Proliferator-activated Receptor γ Ligands Regulate Myeloperoxidase Expression in Macrophages by an Estrogen-dependent Mechanism Involving the -463GA Promoter Polymorphism* , 2004, Journal of Biological Chemistry.

[29]  V. Laudet,et al.  Fibrates increase human REV-ERBalpha expression in liver via a novel peroxisome proliferator-activated receptor response element. , 1999, Molecular endocrinology.

[30]  L. Gudas,et al.  Overexpression of the cellular retinoic acid binding protein-I (CRABP- I) results in a reduction in differentiation-specific gene expression in F9 teratocarcinoma cells , 1991, The Journal of cell biology.

[31]  N. Noy,et al.  All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor , 2009, Molecular and Cellular Biology.

[32]  N. Noy,et al.  A ligand-activated nuclear localization signal in cellular retinoic acid binding protein-II. , 2005, Molecular cell.

[33]  A. Cimini,et al.  Signal transduction pathways involved in PPARβ/δ‐induced neuronal differentiation , 2011, Journal of cellular physiology.

[34]  T. Martin,et al.  The parathyroid hormone-related protein gene and its expression , 1994, Molecular and Cellular Endocrinology.

[35]  K. Storey,et al.  Initiation of neuronal differentiation requires PI3-kinase/TOR signalling in the vertebrate neural tube. , 2010, Developmental biology.

[36]  F. McCormick,et al.  Inhibition of protein synthesis stimulates the transcription of human beta-interferon genes in Chinese hamster ovary cells. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[37]  G. Eichele,et al.  International Union of Pharmacology. LX. Retinoic Acid Receptors , 2006, Pharmacological Reviews.

[38]  J. Gustafsson,et al.  Localization of the peroxisome proliferator-activated receptor in the brain. , 1994, Neuroreport.

[39]  N. Noy,et al.  Retinoic Acid Is a High Affinity Selective Ligand for the Peroxisome Proliferator-activated Receptor β/δ* , 2003, Journal of Biological Chemistry.

[40]  A. Budhu,et al.  Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest , 2002, Molecular and Cellular Biology.

[41]  D. Soprano,et al.  Role of retinoic acid in the differentiation of embryonal carcinoma and embryonic stem cells. , 2007, Vitamins and hormones.