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Retinoic acid in the development, regeneration and maintenance of the nervous system

Key Points

  • Retinoic acid (RA) is involved in the induction of neural differentiation, motor neuron axon outgrowth and neural patterning during development, but there is growing evidence that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration.

  • RA is a metabolic product of vitamin A (retinol) that signals in both a paracrine and an autocrine manner.

  • During development, RA is required for hindbrain patterning and, together with sonic hedgehog and bone morphogenetic proteins, for patterning the dorsoventral axis of the neural tube.

  • RA also induces the differentiation of various types of neurons and glia, by activating the transcription of genes that encode various transcription factors, cell signalling molecules, structural proteins, enzymes and cell-surface receptors. This ability can be harnessed to induce the differentiation of stem cells into neural cell types, which could then be used for therapeutic transplantation.

  • In peripheral nerves, RA stimulates the regenerative response. In this case it does not necessarily act directly on the neuron: Schwann cells and macrophages might be targets of RA.

  • In the mature CNS, RA has a role in the maintenance of plasticity and neural stem cell production. Together with data that implicate a loss of RA signalling in the aetiology of Parkinson's disease, motor neuron disease and Alzheimer's disease, these findings highlight the potential of RA replacement as a therapeutic strategy for treating these conditions.

Abstract

Retinoic acid (RA) is involved in the induction of neural differentiation, motor axon outgrowth and neural patterning. Like other developmental molecules, RA continues to play a role after development has been completed. Elevated RA signalling in the adult triggers axon outgrowth and, consequently, nerve regeneration. RA is also involved in the maintenance of the differentiated state of adult neurons, and disruption of RA signalling in the adult leads to the degeneration of motor neurons (motor neuron disease), the development of Alzheimer's disease and, possibly, the development of Parkinson's disease. The data described here strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration.

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Figure 1: Pathways that are involved in the generation, action and catabolism of retinoic acid (RA).
Figure 2: The effects of retinoic acid (RA) on patterning in the early embryo.
Figure 3: The effects of an excess and/or deficiency of retinoic acid (RA) signalling in neural development.
Figure 4: A summary of some of the molecular and cellular interactions that are induced following peripheral nerve damage (PND).
Figure 5: A summary of the possible role of retinoic acid (RA) in the adult CNS.

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References

  1. Blomhoff, R. & Blomhoff, H. K. Overview of retinoid metabolism and function. J. Neurobiol. 66, 606–630 (2006).

    CAS  PubMed  Google Scholar 

  2. Kawaguchi, R. et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315, 820–825 (2007).

    CAS  PubMed  Google Scholar 

  3. Sandell, L. L. et al. RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes Dev. 21, 1113–1124 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Budhu, A. S. & Noy, N. 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. Mol. Cell Biol. 22, 2632–2641 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bastien, J. & Rochette-Egly, C. Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene 328, 1–16 (2004).

    CAS  PubMed  Google Scholar 

  6. Balmer, J. E. & Blomhoff, R. Gene expression regulation by retinoic acid. J. Lipid Res. 43, 1773–1808 (2002).

    CAS  PubMed  Google Scholar 

  7. Liu, J.-P., Laufer, E. & Jessell, T. M. Assigning the positional identity of spinal motor neurons: rostrocaudal patterning of Hox-c expression by Fgfs, Gdf11, and retinoids. Neuron 32, 997–1012 (2001). This study shows the relationship between three signalling molecules and details how they co-operate in the organization of the anteroposterior axis of the spinal cord.

    CAS  PubMed  Google Scholar 

  8. Maden, M. Retinoid signalling in the development of the central nervous system. Nature Rev. Neurosci. 3, 843–853 (2002).

    CAS  Google Scholar 

  9. Melton, K. R., Iulianella, A. & Trainor, P. A. Gene expression and regulation of hindbrain and spinal cord development. Front. Biosci. 9, 117–138 (2004).

    CAS  PubMed  Google Scholar 

  10. Maden, M., Gale, E., Kostetskii, I. & Zile, M. Vitamin A-deficient quail embryos have half a hindbrain and other neural defects. Curr. Biol. 6, 417–426 (1996). This was the first study to show that RA is involved in the development of the posterior hindbrain and that in its absence this part of the nervous system does not develop.

    CAS  PubMed  Google Scholar 

  11. Wilson, L., Gale, E., Chambers, D. & Maden, M. The role of retinoic acid in the dorsoventral patterning of the spinal cord. Dev. Biol. 269, 433–446 (2004).

    CAS  PubMed  Google Scholar 

  12. Reijntjes, S., Gale, E. & Maden, M. Generating gradients of retinoic acid in the chick embryo: Cyp26C1 expression and a comparative analysis of the Cyp26 enzymes. Dev. Dyn. 230, 509–517 (2004).

    CAS  PubMed  Google Scholar 

  13. Glover, J. C., Renaud, J. S. & Rijli, F. M. Retinoic acid and hindbrain patterning. J. Neurobiol. 66, 705–725 (2006).

    CAS  PubMed  Google Scholar 

  14. Novitch, B. G., Wichterle, H., Jessell, T. M. & Sockanathan, S. A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification. Neuron 40, 81–95 (2003).

    CAS  PubMed  Google Scholar 

  15. Wilson, L. & Maden, M. The mechanisms of dorsoventral patterning in the vertebrate neural tube. Dev. Biol. 282, 1–13 (2005).

    CAS  PubMed  Google Scholar 

  16. Diez del Corral, R. & Storey, K. G. Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis. Bioessays 26, 857–869 (2004).

    PubMed  Google Scholar 

  17. Andrews, P. A. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev. Biol. 103, 28–293 (1984).

    Google Scholar 

  18. Edwards, M. K. S. & McBurney, M. W. The concentration of retinoic acid determines the differentiated cell types formed by a teratocarcinoma cell line. Dev. Biol. 98, 187–191 (1983).

    CAS  PubMed  Google Scholar 

  19. Jones-Villeneuve, E. M. V., McBurney, M. W., Rogers, K. A. & Kalnins, V. I. Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells. J. Cell Biol. 94, 253–262 (1982).

    CAS  PubMed  Google Scholar 

  20. Kuff, E. I. & Fewell, J. W. Induction of neural-like cells and acetylcholinesterase activity in cultures of F9 teratocarcinoma cells treated with retinoic acid and dibutyryl cyclic adenosine monophosphate. Dev. Biol. 77, 103–115 (1980).

    CAS  PubMed  Google Scholar 

  21. Sidell, N., Altman, A., Haussler, M. R. & Seeger, R. C. Effects of retinoic acid (RA) on the growth and phenotypic expression of several human neuroblastoma cell lines. Exp. Cell Res. 148, 21–30 (1983).

    CAS  PubMed  Google Scholar 

  22. Thompson, S. et al. Cloned human teratoma cells differentiate into neuron-like cells and other cell types in retinoic acid. J. Cell Sci. 72, 37–64 (1984).

    CAS  PubMed  Google Scholar 

  23. Maden, M. Role and distribution of retinoic acid during CNS development. Int. Rev. Cytol. 209, 1–77 (2001).

    CAS  PubMed  Google Scholar 

  24. Mizuno, K. et al. SHP-1 is induced in neuronal differentiation of P19 embryonic carcinoma cells. FEBS Lett. 417, 6–12 (1997).

    CAS  PubMed  Google Scholar 

  25. Verani, R. et al. Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid. J. Neurochem. 100, 242–250 (2007).

    CAS  PubMed  Google Scholar 

  26. Dziewczapolski, G., Lie, D. C., Ray, J., Gage, F. H. & Shults, C. W. Survival and differentiation of adult rat-derived neural progenitor cells transplanted to the striatum of hemiparkinsonian rats. Exp. Neurol. 183, 653–664 (2003).

    CAS  PubMed  Google Scholar 

  27. Bosch, M. et al. Induction of GABAergic phenotype in a neural stem cell line for transplantation in an excitotoxic model of Huntington's disease. Exp. Neurol. 190, 42–58 (2004).

    CAS  PubMed  Google Scholar 

  28. Li, Q. et al. LinCD34 bone marrow cells from adult mice can differentiate into neural-like cells. Neurosci. Lett. 408, 51–56 (2006).

    CAS  PubMed  Google Scholar 

  29. Ikeda, R. et al. Transplantation of neural cells derived from retinoic acid-treated cynomolgus monkey embryonic stem cells successfully improved motor function of hemiplegic mice with experimental brain injury. Neurobiol. Dis. 20, 38–48 (2005). This study provides an example of an application of RA-differentiated stem cells.

    CAS  PubMed  Google Scholar 

  30. Nonaka, M. et al. Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats. Neurol. Res. 26, 265–272 (2004).

    PubMed  Google Scholar 

  31. Mimura, T., Dezawa, M., Kanno, H., Sawada, H. & Yamamoto, I. Peripheral nerve regeneration by transplantation of bone marrow stromal cell-derived Schwann cells in adult rats. J. Neurosurg. 101, 806–812 (2004).

    PubMed  Google Scholar 

  32. Chiba, S., Iwasaki, Y., Sekino, H. & Suzuki, N. Transplantation of motoneuron-enriched neural cells derived from mouse embryonic stem cells improves motor function of hemiplegic mice. Cell Transplant. 12, 457–468 (2003).

    PubMed  Google Scholar 

  33. Chiba, S. et al. Anatomical and functional recovery by embryonic stem cell-derived neural tissue of a mouse model of brain damage. J. Neurol. Sci. 219, 107–117 (2004).

    CAS  PubMed  Google Scholar 

  34. Guidato, S., Prin, F. & Guthrie, S. Somatic motoneurone specification in the hindbrain: the influence of somite-derived signals, retinoic acid and Hoxa3. Development 130, 2981–2996 (2003).

    CAS  PubMed  Google Scholar 

  35. Swindell, E. C. et al. Complementary domains of retinoic acid production and degradation in the early chick embryo. Dev. Biol. 216, 282–296 (1999).

    CAS  PubMed  Google Scholar 

  36. Blentic, A., Gale, E. & Maden, M. Retinoic acid signalling centres in the avian embryo identified by sites of expression of synthesising and catabolising enzymes. Dev. Dyn. 227, 114–127 (2003).

    CAS  PubMed  Google Scholar 

  37. Niederreither, K., McCaffery, P., Drager, U. C., Chambon, P. & Dolle, P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech. Dev. 62, 67–78 (1997).

    CAS  PubMed  Google Scholar 

  38. Maden, M., Sonneveld, E., van der Saag, P. T. & Gale, E. The distribution of endogenous retinoic acid in the chick embryo: implications for developmental mechanisms. Development 125, 4133–4144 (1998).

    CAS  PubMed  Google Scholar 

  39. Grapin-Botton, A., Bonnon, M.-A., Sieweke, M. & Le Douarin, N. M. Defined concentrations of a posteriorizing signal are critical for MafB/Kreisler segmental expression in the hindbrain. Development 125, 1173–1181 (1998).

    CAS  PubMed  Google Scholar 

  40. Guidato, S., Barrett, C. & Guthrie, S. Patterning of motor neurons by retinoic acid in the chick embryo hindbrain in vitro. Mol. Cell Neurosci. 23, 81–95 (2003).

    CAS  PubMed  Google Scholar 

  41. Maden, M., Gale, E. & Zile, M. The role of vitamin A in the development of the central nervous system. J. Nutr. 128, 471S–475S (1998).

    CAS  PubMed  Google Scholar 

  42. Ensini, M., Tsuchida, T., Betling, H.-G. & Jessell, T. The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm. Development 125, 969–982 (1998).

    CAS  PubMed  Google Scholar 

  43. Ji, S. J. et al. Mesodermal and neuronal retinoids regulate the induction and maintenance of limb-innervating spinal motor neurons. Dev. Biol. 297, 249–261 (2006).

    CAS  PubMed  Google Scholar 

  44. Zhao, D. et al. Molecular identification of a major retinoic acid-synthesising enzyme, a retinaldehyde-specific dehydrogenase. Eur. J. Biochem. 240, 15–22 (1996).

    CAS  PubMed  Google Scholar 

  45. Sockanathan, S. & Jessell, T. M. Motor neuron-derived retinoid signalling specifies the subtype identity of spinal motor neurons. Cell 94, 503–514 (1998). This paper reveals the role of RA in the generation of presumptive motor neurons in the spinal cord and in the further differentiation of this cell type.

    CAS  PubMed  Google Scholar 

  46. Vermot, J. et al. Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons. Development 132, 1611–1621 (2005).

    CAS  PubMed  Google Scholar 

  47. Sockanathan, S., Perlmann, T. & Jessell, T. M. Retinoid receptor signaling in postmitotic motor neurons regulates rostrocaudal positional identity and axonal projection pattern. Neuron 40, 97–111 (2003).

    CAS  PubMed  Google Scholar 

  48. Zhelyaznik, N., Schrage, K., McCaffery, P. & Mey, J. Activation of retinoic acid signalling after sciatic nerve injury: up-regulation of cellular retinoid binding proteins. Eur. J. Neurosci. 18, 1033–1040 (2003).

    PubMed  Google Scholar 

  49. So, P. L. et al. Interactions between retinoic acid, nerve growth factor and sonic hedgehog signalling pathways in neurite outgrowth. Dev. Biol. 298, 167–175 (2006).

    CAS  PubMed  Google Scholar 

  50. Corcoran, J. P., So, P. L. & Maden, M. Disruption of the retinoid signalling pathway causes a deposition of amyloid β in the adult rat brain. Eur. J. Neurosci. 20, 896–902 (2004). This study shows that, in the absence of RA, the cellular characteristics of Alzheimer's disease appear in rats.

    PubMed  Google Scholar 

  51. Corcoran, J. & Maden, M. Nerve growth factor acts via retinoic acid synthesis to stimulate neurite outgrowth. Nature Neurosci. 2, 307–308 (1999).

    CAS  PubMed  Google Scholar 

  52. Zhelyaznik, N. & Mey, J. Regulation of retinoic acid receptors α, β and retinoid X receptor α after sciatic nerve injury. Neuroscience 141, 1761–1774 (2006).

    CAS  PubMed  Google Scholar 

  53. Mey, J., Schrage, K., Wessels, I. & Vollpracht-Crijns, I. Effects of inflammatory cytokines IL-1β, IL-6, and TNFα on the intracellular localization of retinoid receptors in Schwann cells. Glia 55, 152–164 (2007).

    PubMed  Google Scholar 

  54. Corcoran, J., Shroot, B., Pizzey, J. & Maden, M. The role of retinoic acid receptors in neurite outgrowth from different populations of embryonic mouse dorsal root ganglia. J. Cell Sci. 113, 2567–2574 (2000).

    CAS  PubMed  Google Scholar 

  55. Corcoran, J. et al. Retinoic acid receptor β2 and neurite outgrowth in the adult mouse spinal cord in vitro. J. Cell Sci. 115, 3779–3786 (2002).

    CAS  PubMed  Google Scholar 

  56. Wong, L. F. et al. Retinoic acid receptor β2 promotes functional regeneration of sensory axons in the spinal cord. Nature Neurosci. 9, 243–250 (2006). This study provided the first in vivo demonstration that upregulating a RA receptor leads to the induction of nerve regeneration and functional recovery.

    CAS  PubMed  Google Scholar 

  57. Akazawa, C. et al. The upregulated expression of sonic hedgehog in motor neurons after rat facial nerve axotomy. J. Neurosci. 24, 7923–7930 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Mey, J. Retinoic acid as a regulator of cytokine signaling after nerve injury. Z. Naturforsch. [C ] 56, 163–176 (2001).

    CAS  Google Scholar 

  59. Mey, J. New therapeutic target for CNS injury? The role of retinoic acid signaling after nerve lesions. J. Neurobiol. 66, 757–779 (2006).

    CAS  PubMed  Google Scholar 

  60. Taha, M. O. et al. Effect of retinoic acid on tibial nerve regeneration after anastomosis in rats: histological and functional analyses. Transplant. Proc. 36, 404–408 (2004).

    CAS  PubMed  Google Scholar 

  61. Arrieta, O. et al. Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice. Eur. J. Clin. Invest. 35, 201–207 (2005).

    CAS  PubMed  Google Scholar 

  62. Kern, J. et al. Characterization of retinaldehyde dehydrogenase-2 induction in NG2-positive glia after spinal cord contusion injury. Int. J. Dev. Neurosci. 25, 7–16 (2007).

    CAS  PubMed  Google Scholar 

  63. Mey, J. et al. Retinoic acid synthesis by a population of NG2-positive cells in the injured spinal cord. Eur. J. Neurosci. 21, 1555–1568 (2005).

    PubMed  Google Scholar 

  64. Charytoniuk, D. A. et al. Distribution of bone morphogenetic protein and bone morphogenetic protein receptor transcripts in the rodent nervous system and up-regulation of bone morphogenetic protein receptor type II in hippocampal dentate gyrus in a rat model of global cerebral ischemia. Neuroscience 100, 33–43 (2000).

    CAS  PubMed  Google Scholar 

  65. Yip, P. K. et al. Lentiviral vector expressing retinoic acid receptor β2 promotes recovery of function after corticospinal tract injury in the adult rat spinal cord. Hum. Mol. Genet. 15, 3107–3118 (2006).

    CAS  PubMed  Google Scholar 

  66. Krezel, W., Kastner, P. & Chambon, P. Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience 89, 1291–1300 (1999).

    CAS  PubMed  Google Scholar 

  67. Wietrzych, M. et al. Working memory deficits in retinoid X receptor γ-deficient mice. Learn. Mem. 12, 318–326 (2005).

    PubMed  PubMed Central  Google Scholar 

  68. Zetterstrom, R. H. et al. Role of retinoids in the CNS: differential expression of retinoid binding protein and receptors and evidence for presence of retinoic acid. Eur. J. Neurosci. 11, 407–416 (1999).

    CAS  PubMed  Google Scholar 

  69. Thompson, H. G., Maynard, T. M., Shatzmiller, R. A. & LaMantia, A. S. Retinoic acid signaling at sites of plasticity in the mature central nervous system. J. Comp. Neurol. 452, 228–241 (2002). This study reveals the sites in the adult brain where RA signalling continues to be activated.

    Google Scholar 

  70. Asson-Batres, M. A. & Smith, W. B. Localization of retinaldehyde dehydrogenases and retinoid binding proteins to sustentacular cells, glia, Bowman's gland cells, and stroma: potential sites of retinoic acid synthesis in the postnatal rat olfactory organ. J. Comp. Neurol. 496, 149–171 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gustafson, A.-L., Eriksson, U. & Dencker, L. CRBPI and CRABPI localisation during olfactory nerve development. Dev. Brain Res. 114, 121–126 (1999).

    CAS  Google Scholar 

  72. Kurlandsky, S. B., Gamble, M. V., Ramakrishnan, R. & Blaner, W. S. Plasma delivery of retinoic acid to tissues in the rat. J. Biol. Chem. 270, 17850–17857 (1995).

    CAS  PubMed  Google Scholar 

  73. Le, D. F., Debruyne, D., Albessard, F., Barre, L. & Defer, G. L. Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of rat. Drug Metab. Dispos. 28, 205–208 (2000).

    Google Scholar 

  74. Werner, E. A. & DeLuca, H. F. Retinoic acid is detected at relatively high levels in the CNS of adult rats. Am. J. Physiol. Endocrinol. Metab. 282, E672–E678 (2002).

    CAS  PubMed  Google Scholar 

  75. Connor, M. J. & Sidell, N. Retinoic acid synthesis in normal and Alzheimer diseased brain and human neural cells. Mol. Chem. Neuropathol. 30, 239–252 (1997).

    CAS  PubMed  Google Scholar 

  76. Dev, S., Adler, A. J. & Edwards, R. B. Adult rabbit brain synthesizes retinoic acid. Brain Res. 632, 325–328 (1993).

    CAS  PubMed  Google Scholar 

  77. Kane, M. A., Chen, N., Sparks, S. & Napoli, J. L. Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS. Biochem. J. 388, 363–369 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Wagner, E., Luo, T. & Drager, U. C. Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems. Cereb. Cortex 12, 1244–1253 (2002).

    PubMed  Google Scholar 

  79. McCaffery, P. & Drager, U. C. High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. Proc. Natl Acad. Sci. USA 91, 7772–7776 (1994). This study found that high levels of RA synthesis are seen specifically in dopaminergic neurons in the adult brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Smith, D., Wagner, E., Koul, O., McCaffery, P. & Drager, U. C. Retinoic acid synthesis for the developing telencephalon. Cereb. Cortex 11, 894–905 (2001).

    CAS  PubMed  Google Scholar 

  81. Luo, T., Wagner, E., Grun, F. & Drager, U. C. Retinoic acid signaling in the brain marks formation of optic projections, maturation of the dorsal telencephalon, and function of limbic sites. J. Comp. Neurol. 470, 297–316 (2004).

    CAS  PubMed  Google Scholar 

  82. McCaffery, P., Zhang, J. & Crandall, J. E. Retinoic acid signaling and function in the adult hippocampus. J. Neurobiol. 66, 780–791 (2006).

    CAS  PubMed  Google Scholar 

  83. Misner, D. L. et al. Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Proc. Natl Acad. Sci. USA 98, 11714–11719 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Sakai, Y., Crandall, J. E., Brodsky, J. & McCaffery, P. 13-cis retinoic acid (accutane) suppresses hippocampal cell survival in mice. Ann. NY Acad. Sci. 1021, 436–440 (2004).

    CAS  PubMed  Google Scholar 

  85. Denisenko-Nehrbass, N. I., Jarvis, E., Scharff, C., Nottebohm, F. & Mello, C. V. Site-specific retinoic acid production in the brain of adult songbirds. Neuron 27, 359–370 (2000).

    CAS  PubMed  Google Scholar 

  86. Denisenko-Nehrbass, N. I. & Mello, C. V. Molecular targets of disulfiram action on song maturation in zebra finches. Brain Res. Mol. Brain Res. 87, 246–250 (2001).

    CAS  PubMed  Google Scholar 

  87. Wolbach, S. B. & Howe, P. R. Tissue changes following deprivation of fat soluble A vitamin. J. Exp. Med. 42, 753–777 (1925).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Asson-Batres, M. A., Zeng, M. S., Savchenko, V., Aderoju, A. & McKanna, J. Vitamin A deficiency leads to increased cell proliferation in olfactory epithelium of mature rats. J. Neurobiol. 54, 539–554 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hagglund, M., Berghard, A., Strotmann, J. & Bohm, S. Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice. J. Neurosci. 26, 3281–3291 (2006).

    PubMed  PubMed Central  Google Scholar 

  90. Yee, K. K. & Rawson, N. E. Retinoic acid enhances the rate of olfactory recovery after olfactory nerve transection. Brain Res. Dev. Brain Res. 124, 129–132 (2000).

    CAS  PubMed  Google Scholar 

  91. Etchamendy, N. et al. Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behav. Brain Res. 145, 37–49 (2003).

    CAS  PubMed  Google Scholar 

  92. Cocco, S. et al. Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115, 475–482 (2002). This paper shows that RA is involved in learning and memory in the adult brain.

    CAS  PubMed  Google Scholar 

  93. Chiang, M.-Y. et al. An essential role for retinoid receptors RARβ and RXRγ in long-term potentiation and depression. Neuron 21, 1353–1361 (1998). This was the first study to reveal a role for RA signalling in hippocampal function in adults.

    CAS  PubMed  Google Scholar 

  94. Crandall, J. et al. 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc. Natl Acad. Sci. USA 101, 5111–5116 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Iniguez, M. A. et al. Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin). Brain Res. Mol. Brain Res. 27, 205–214 (1994).

    CAS  PubMed  Google Scholar 

  96. Wang, Y.-Z. & Christakos, S. Retinoic acid regulates the expression of the calcium binding protein, calbindin-D28K. Mol. Endocrinol. 9, 1510–1521 (1995).

    CAS  PubMed  Google Scholar 

  97. Hernandez-Pinto, A. M., Puebla-Jimenez, L. & Rilla-Ferreiro, E. A vitamin A-free diet results in impairment of the rat hippocampal somatostatinergic system. Neuroscience 141, 851–861 (2006).

    CAS  PubMed  Google Scholar 

  98. Berse, B. & Blusztajn, J. K. Coordinated up-regulation of choline acetyltransferase and vesicular acetylcholine transporter gene expression by the retinoic acid receptor α, cAMP, and leukemia inhibitory factor/ciliary neurotrophic factor signaling pathways in a murine septal cell line. J. Biol. Chem. 270, 22101–22104 (1995).

    CAS  PubMed  Google Scholar 

  99. Shudo, K., Kagechika, H., Yamazaki, N., Igarashi, M. & Tateda, C. A synthetic retinoid Am80 (tamibarotene) rescues the memory deficit caused by scopolamine in a passive avoidance paradigm. Biol. Pharm. Bull. 27, 1887–1889 (2004).

    CAS  PubMed  Google Scholar 

  100. Samad, T. A., Krezel, W., Chambon, P. & Borrelli, E. Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor–retinoid X receptor family. Proc. Natl Acad. Sci. USA 94, 14349–14354 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Krezel, W. et al. Impaired locomotion and dopamine signalling in retinoid receptor mutant mice. Science 279, 863–867 (1998). This paper shows that RA signalling is involved in striatal function in the adult brain.

    CAS  PubMed  Google Scholar 

  102. Zetterstrom, R. H. et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248–250 (1997).

    CAS  PubMed  Google Scholar 

  103. Krauss, J. K., Mohandjer, M., Wakhloo, A. K. & Mundinger, F. Dystonia and akinesia due to pallidoputaminal lesions after disulphiram treatment. Mov. Dis. 6, 166–170 (1991).

    CAS  Google Scholar 

  104. Laplane, D., Attal, N., Sauron, B., de Billy, A. & Dubois, B. Lesions of basal ganglia due to disulphiram neurotoxicity. J. Neurol. Neurosurg. Psychiatr. 55, 925–929 (1992).

    CAS  Google Scholar 

  105. Deltour, L., Ang, H. L. & Duester, G. Ethanol inhibition of retinoic acid synthesis as a potential mechanism for fetal alcohol syndrome. FASEB J. 10, 1050–1057 (1996).

    CAS  PubMed  Google Scholar 

  106. Wohl, C. A. & Weiss, S. Retinoic acid enhances neural proliferation and astroglial differentiation in cultures of CNS stem cell-derived precursors. J. Neurobiol. 37, 281–290 (1998).

    CAS  PubMed  Google Scholar 

  107. Takahashi, J., Palmer, T. D. & Gage, F. H. Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J. Neurobiol. 38, 65–81 (1999).

    CAS  PubMed  Google Scholar 

  108. Wang, T. W., Zhang, H. & Parent, J. M. Retinoic acid regulates postnatal neurogenesis in the murine subventricular zone–olfactory bulb pathway. Development 132, 2721–2732 (2005). This study reveals the effects of RA in promoting nerve cell production from neural stem cells.

    CAS  PubMed  Google Scholar 

  109. Giardino, L., Bettelli, C. & Calza, L. In vivo regulation of precursor cells in the subventricular zone of adult rat brain by thyroid hormone and retinoids. Neurosci. Lett. 295, 17–20 (2000).

    CAS  PubMed  Google Scholar 

  110. Corcoran, J., So, P.-L. & Maden, M. Absence of retinoids can induce motoneuron disease in the adult rat and a retinoid defect is present in motoneuron disease patients. J. Cell Sci. 115, 4735–4741 (2002).

    CAS  PubMed  Google Scholar 

  111. Husson, M. et al. Triiodothyronine administration reverses vitamin A deficiency-related hypo-expression of retinoic acid and triiodothyronine nuclear receptors and of neurogranin in rat brain. Br. J. Nutr. 90, 191–198 (2003).

    CAS  PubMed  Google Scholar 

  112. Enderlin, V. et al. Age-related decreases in mRNA for nuclear receptors and target genes are reversed by retinoic acid treatment. Neurosci. Lett. 229, 125–129 (1997). This was the first study to show a decline in RA receptor expression during ageing.

    CAS  PubMed  Google Scholar 

  113. Hart, E. B., Miller, W. S. & McCollum, E. V. Further studies on the nutritive deficiencies of wheat and grain mixtures and the pathological conditions produced in swine by their use. J. Biol. Chem. 25, 239–260 (1916).

    CAS  Google Scholar 

  114. Alberle, S. B. D. Neurological disturbances in rats reared on diets deficient in vitamin A. J. Nutr. 7, 445–461 (1934).

    Google Scholar 

  115. Mellanby, E. Diseases produced and prevented by certain food constituents. J. Am. Med. Assoc. 96, 325–331 (1931).

    Google Scholar 

  116. Hughes, J. S., Lienhardt, H. F. & Aubel, C. E. Nerve degeneration resulting from a vitaminosis A. J. Nutr. 2, 183–186 (1929).

    CAS  Google Scholar 

  117. Irving, J. T. & Richards, M. B. Early lesions of vitamin A deficiency. J. Physiol. 94, 307–321 (1938).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Malaspina, A., Kaushik, N. & De Belleroche, J. Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J. Neurochem. 77, 132–145 (2001).

    CAS  PubMed  Google Scholar 

  119. Jiang, Y. M. et al. Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis. Ann. Neurol. 57, 236–251 (2005).

    CAS  PubMed  Google Scholar 

  120. Molina, J. A. et al. Serum levels of β-carotene, α-carotene, and vitamin A in patients with amyotrophic lateral sclerosis. Acta Neurol. Scand. 99, 315–317 (1999).

    CAS  PubMed  Google Scholar 

  121. Saga, Y. et al. Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRγ1 isoform. Genes Cells 4, 219–228 (1999).

    CAS  PubMed  Google Scholar 

  122. Husson, M. et al. Retinoic acid normalizes nuclear receptor mediated hypo-expression of proteins involved in β-amyloid deposits in the cerebral cortex of vitamin A deprived rats. Neurobiol. Dis. 23, 1–10 (2006). This study shows how RA could be used in the adult brain to return the RA status in vitamin-A-deprived rats to normal.

    CAS  PubMed  Google Scholar 

  123. Goodman, A. B. Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. J. Cell Physiol. 209, 598–603 (2006).

    CAS  PubMed  Google Scholar 

  124. Maury, C. P. J. & Teppo, A.-M. Immunodetection of protein composition in cerebral amyloid extracts in Alzheimer's disease: enrichment of retinol-binding protein. J. Neurol. Sci. 80, 221–228 (1987).

    CAS  PubMed  Google Scholar 

  125. Culvenor, J. G. et al. Presenilin 2 expression in neuronal cells: induction during differentiation of embryonic carcinoma cells. Exp. Cell Res. 255, 192–206 (2000).

    CAS  PubMed  Google Scholar 

  126. Hong, C. S. et al. Contrasting role of presenilin-1 and presenilin-2 in neuronal differentiation in vitro. J. Neurosci. 19, 637–643 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lahiri, D. K. & Nall, C. Promoter activity of the gene encoding the β-amyloid precursor protein is up-regulated by growth factors, phorbol ester, retinoic acid and interleukin-1. Brain Res. Mol. Brain Res. 32, 233–240 (1995).

    CAS  PubMed  Google Scholar 

  128. Yang, Y., Quitschke, W. W. & Brewer, G. J. Upregulation of amyloid precursor protein gene promoter in rat primary hippocampal neurons by phorbol ester, IL-1 and retinoic acid, but not by reactive oxygen species. Mol. Brain Res. 60, 40–49 (1998).

    CAS  PubMed  Google Scholar 

  129. Pan, J. B., Monteggia, L. M. & Giordano, T. Altered levels and splicing of the amyloid precursor protein in the adult rat hippocampus after treatment with DMSO or retinoic acid. Brain Res. Mol. Brain Res. 18, 259–266 (1993).

    CAS  PubMed  Google Scholar 

  130. Fahrenholz, F. & Postina, R. α-secretase activation — an approach to Alzheimer's disease therapy. Neurodegener. Dis. 3, 255–261 (2006).

    CAS  PubMed  Google Scholar 

  131. Prinzen, C., Muller, U., Endres, K., Fahrenholz, F. & Postina, R. Genomic structure and functional characterization of the human ADAM10 promoter. FASEB J. 19, 1522–1524 (2005).

    CAS  PubMed  Google Scholar 

  132. Satoh, J. & Kuroda, Y. Amyloid precursor protein β-secretase (BACE) mRNA expression in human neural cell lines following induction of neuronal differentiation and exposure to cytokines and growth factors. Neuropathology 20, 289–296 (2000).

    CAS  PubMed  Google Scholar 

  133. Gao, Y. & Pimplikar, S. W. The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl Acad. Sci. USA 98, 14979–14984 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Yoshikawa, K., Aizawa, T. & Hayashi, Y. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359, 64–67 (1992).

    CAS  PubMed  Google Scholar 

  135. Ono, K. et al. Vitamin A exhibits potent antiamyloidogenic and fibril-destabilizing effects in vitro. Exp. Neurol. 189, 380–392 (2004).

    CAS  PubMed  Google Scholar 

  136. Sahin, M., Karauzum, S. B., Perry, G., Smith, M. A. & Aliciguzel, Y. Retinoic acid isomers protect hippocampal neurons from amyloid-β induced neurodegeneration. Neurotox. Res. 7, 243–250 (2005). This study provides an example of the protective effect that RA has on amyloid-β-induced cell death.

    CAS  PubMed  Google Scholar 

  137. Whitehouse, P. J. et al. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239 (1982).

    CAS  PubMed  Google Scholar 

  138. Pedersen, W. A., Kloczewiak, M. A. & Blusztajn, J. K. Amyloid-β protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain. Proc. Natl Acad. Sci. USA 93, 8068–8071 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Coleman, B. A. & Taylor, P. Regulation of acetylcholinesterase expression during neuronal differentiation. J. Biol. Chem. 271, 4410–4416 (1996).

    CAS  PubMed  Google Scholar 

  140. Hill, D. R. & Robertson, K. A. Characterisation of the colinergic neuronal differentiation of the human neuroblastoma cell line LAN-5 after treatment with retinoic acid. Dev. Brain Res. 102, 53–67 (1997).

    CAS  Google Scholar 

  141. Parnas, D. & Linial, M. Cholinergic properties of neurons differentiated from an embryonal carcinoma cell-line (P19). Int. J. Dev. Neurosci. 13, 767–781 (1995).

    CAS  PubMed  Google Scholar 

  142. Pedersen, W. A., Berse, B., Schuler, U., Wainer, B. H. & Blusztajn, J. K. All-trans- and 9-cis-retinoic acid enhance the cholinergic properties of a murine septal cell line: evidence that the effects are mediated by activation of retinoic acid receptor-α. J. Neurochem. 65, 50–58 (1995).

    CAS  PubMed  Google Scholar 

  143. Sidell, N., Lucas, C. A. & Kreutzberg, G. W. Regulation of acetylcholinesterase acvitity by retinoic acid in a human neuroblastoma cell line. Exp. Cell Res. 155, 305–309 (1984).

    CAS  PubMed  Google Scholar 

  144. Sharpe, C. & Goldstone, K. Retinoid signalling acts during the gastrula stages to promote primary neurogenesis. Int. J. Dev. Biol. 44, 463–470 (2000).

    CAS  PubMed  Google Scholar 

  145. Blumberg, B. et al. An essential role for retinoid signalling in anteroposterior neural patterning. Development 124, 373–379 (1997). This study shows how normal, upregulated and downregulated RA signalling affects on the expression of various genes in the anteroposterior axis of the developing CNS.

    CAS  PubMed  Google Scholar 

  146. Franco, P. G., Paganelli, A. R., Lopez, S. L. & Carrasco, A. E. Functional association of retinoic acid and hedgehog signaling in Xenopus primary neurogenesis. Development 126, 4257–4265 (1999).

    CAS  PubMed  Google Scholar 

  147. Papalopulu, N. & Kintner, C. A posteriorising factor, retinoic acid, reveals that anteroposterior patterning controls the timing of neuronal differentiation in Xenopus neuroectoderm. Development 122, 3409–3418 (1996).

    CAS  PubMed  Google Scholar 

  148. Sharpe, C. R. & Goldstone, K. Retinoid receptors promote primary neurogenesis in Xenopus. Development 124, 515–523 (1997).

    CAS  PubMed  Google Scholar 

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Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 8, 755–765 (2007). https://doi.org/10.1038/nrn2212

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