Role of retinoid signalling in the adult brain

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Abstract

Vitamin A (all-trans-retinol) is the parent compound of a family of natural and synthetic compounds, the retinoids. Retinoids regulate gene transcription in numerous cells and tissues by binding to nuclear retinoid receptor proteins, which act as transcription factors. Much of the research conducted on retinoid signalling in the nervous system has focussed on developmental effects in the embryonic or early postnatal brain. Here, we review the increasing body of evidence indicating that retinoid signalling plays an important role in the function of the mature brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids. Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases.

Introduction

Vitamin A and its derivatives, the retinoids, regulate the growth, survival, and differentiation of many cell types. To date, much of the research conducted on Vitamin A and retinoids in the nervous system has focussed on embryonic or early postnatal brain development. It is now well established that retinoids regulate genes which control neuronal differentiation, neurite outgrowth, and the patterning of the anteroposterior axis of the neural tube. These effects likely account for the teratogenic effects of Vitamin A (for recent reviews see Maden, 2002, McCaffery et al., 2003). More recently, evidence has emerged that retinoid signalling may also be required for several aspects of adult brain function (see also Mey and McCaffery, 2004).

We begin this review by outlining the pathways of retinoid metabolism and the localization of components of the retinoid signalling cascade in the adult brain. We then consider the evidence linking retinoid signalling pathways to normal neuronal function and how deficits in retinoid signalling may contribute to the pathology of Alzheimer's disease, schizophrenia and depression. The effects of retinoids are mediated by specific nuclear receptors which act as transcription factors to alter gene expression. However, non-transcriptionally mediated effects of retinoids have also been reported. For example, in the retina retinoic acid acts as a light-signalling neuromodulator and regulates gap junction-mediated coupling of retinal neurons (reviewed by Weiler et al., 2001). Our focus in this review is primarily on distinguishing evidence for retinoid-regulated control of neuronal gene expression in adult neurones, from the retinoid effects on developmental processes of neurogenesis or neurodifferentiation.

This exciting new area of neuroscience research highlights the potential importance of adequate nutritional Vitamin A status for adult brain function. Normally, our nutritional requirements for Vitamin A can be adequately met by a well balanced diet. Dietary excess has only rarely been reported, for example, in the unusual case of toxicity resulting from the consumption of polar bear liver (Rodahl and Moore, 1943). Since retinoids readily enter the central nervous system (Bendich and Langseth, 1989, Snodgrass, 1992), Vitamin A neurotoxicity in adults is possible from excessive consumption of supplements (e.g. Wieland et al., 1971, Restak, 1972). A prominent symptom of hypervitaminosis A in adults is headaches caused by increased intracranial pressure due to brain swelling resulting in pseudotumour cerebri (Snodgrass, 1992). The mechanism by which hypervitaminosis A causes increased intracranial pressure is unknown but it can eventually lead to coma and death (Macapinlac and Olson, 1981). The incidence of Vitamin A toxicity is relatively rare when compared to the incidence of Vitamin A deficiency (VAD) (Bendich and Langseth, 1989). Worldwide, Vitamin A deficiency is the most common micronutrient deficiency. Very little is known about the cellular effects of VAD or excess exogenous retinoids on the adult human brain. In this review we will summarize the data available, from in vitro and in vivo animal models, which suggest that retinoid signalling pathways are important for adult neuronal function in health and disease.

Section snippets

Retinoid metabolism in the adult nervous system

Animal-derived foods contain preformed Vitamin A predominantly as retinyl esters. Plant-derived foods contain pro-Vitamin A carotenoids, such as β-carotene. The majority of preformed Vitamin A and pro-Vitamin A carotenoids are converted to all-trans-retinol (Vitamin A alcohol) by a series of reactions in both the intestinal lumen and mucosa. Once absorbed by the enterocyte, retinol is re-esterified and packaged with other dietary lipids into chylomicrons for transport to the liver. The liver is

Neuronal targets of retinoid-regulated gene expression

We have surveyed the literature for evidence that neuronal specific genes can be regulated by retinoids (Table 2). By and large, the evidence reported here is taken from in vitro cell systems that are models of neuronal differentiation. Many are pluripotent cells that under the influence of ATRA differentiate to a neuronal phenotype. For the purposes of this review, genes involved in neuronal differentiation and maturation pathways, or those that are part of the retinoid signalling cascade

Physiological role of retinoids in hippocampal function

A role for ATRA in the physiological function of the hippocampus is suggested by the presence of components of retinoid signalling pathways (Table 1). RALDH2 protein, one of the enzymes that synthesizes RA, is restricted to the meninges surrounding the hippocampus in the adult mouse brain (Wagner et al., 2002). Immunoreactivity for the binding proteins CRBP-I and CRABP-I immunoreactivity has been demonstrated in the dendritic layers of the hippocampal formation and the dentate gyrus (

Physiological role of retinoids in dopaminergic systems

Dopaminergic neurones are found principally in the midbrain (substantia nigra and ventral tegmental area) and the major dopaminergic pathways project from the midbrain to the striatum, the frontal cortex and the limbic system. The distribution of dopaminergic pathways is consistent with the multiple roles ascribed to dopamine including coordination of movement, reward and emotional processing. Interestingly, key components of retinoid signalling, including RALDH, RARs and RA binding proteins,

Alzheimer's

Retinoid signalling pathways have been implicated in the pathology of Alzheimer's disease (AD) (Goodman and Pardee, 2003). Clinically, AD is characterized by progressive memory impairment and deteriorating cognitive ability. The involvement of RA in cognitive functions, such as learning and memory, has been reported (Section 4.2). The disease is also defined by the formation of amyloid plaques, the presence of neurofibrillary tangles, and ultimately neuronal loss. Familial AD has been linked to

Summary

Clearly, retinoid signalling has a physiological role in synaptic plasticity and learning and memory behaviours. Vitamin A deprivation in adult mice and rats highlight the importance of adequate Vitamin A status for such cognitive functions; but the precise targets of retinoid signalling pathways underlying these altered behaviours remain to be identified.

Given the large number of neuronal genes that could potentially be transcriptionally regulated by retinoids in the adult brain, surprisingly

Acknowledgement

We are grateful to Dr. Chris Bailey and Ms. Kally O’Reilly for their comments on earlier versions of this manuscript.

References (200)

  • D.S. Castro et al.

    Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells

    J. Biol. Chem.

    (2001)
  • M. Ceccarini et al.

    Expression of dystrophin-associated proteins during neuronal differentiation of P19 embryonal carcinoma cells

    Neuromuscul. Disord.

    (2002)
  • A. Cedazo-Minguez et al.

    Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures

    Neuroscience

    (2001)
  • D. Centonze et al.

    Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum

    Neuroscience

    (2004)
  • M.Y. Chiang et al.

    An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression

    Neuron

    (1998)
  • F.C. Chiu et al.

    Expression of neurofilament proteins during retinoic acid-induced differentiation of P19 embryonal carcinoma cells

    Brain Res. Mol. Brain Res.

    (1995)
  • S. Cho et al.

    Retinoic acid regulates gonadotropin-releasing hormone (GnRH) release and gene expression in the rat hypothalamic fragments and GT1-1 neuronal cells in vitro

    Brain Res. Mol. Brain Res.

    (1998)
  • S. Cho et al.

    9-cis-Retinoic acid represses transcription of the gonadotropin-releasing hormone (GnRH) gene via proximal promoter region that is distinct from all-trans-retinoic acid response element

    Brain Res. Mol. Brain Res.

    (2001)
  • S. Cho et al.

    A functional retinoic acid response element (RARE) is present within the distal promoter of the rat gonadotropin-releasing hormone (GnRH) gene

    Brain Res. Mol. Brain Res.

    (2001)
  • S. Cocco et al.

    Vitamin A deficiency produces spatial learning and memory impairment in rats

    Neuroscience

    (2002)
  • B.A. Coleman et al.

    Regulation of acetylcholinesterase expression during neuronal differentiation

    J. Biol. Chem.

    (1996)
  • J.G. Culvenor et al.

    Presenilin 2 expression in neuronal cells: induction during differentiation of embryonic carcinoma cells

    Exp. Cell Res.

    (2000)
  • S. Dev et al.

    Adult rabbit brain synthesizes retinoic acid

    Brain Res.

    (1993)
  • V. Dolezal et al.

    Stimuli that induce a cholinergic neuronal phenotype of NG108-15 cells upregulate ChAT and VAChT mRNAs but fail to increase VAChT protein

    Brain Res. Bull.

    (2001)
  • D. Dong et al.

    Distinct roles for cellular retinoic acid binding proteins I and II in regulating signaling by retinoic acid

    J. Biol. Chem.

    (1999)
  • J.R. Dyck et al.

    Specific activation of the Na+/H+ exchanger gene during neuronal differentiation of embryonal carcinoma cells

    J. Biol. Chem.

    (1995)
  • M. Dziedzicka-Wasylewska et al.

    Neuronal cell lines transfected with the dopamine D2 receptor gene promoter as a model for studying the effects of antidepressant drugs

    Brain Res. Mol. Brain Res.

    (2004)
  • S. Ebihara et al.

    Mouse vesicular GABA transporter gene: genomic organization, transcriptional regulation and chromosomal localization

    Brain Res. Mol. Brain Res.

    (2003)
  • J.B. Eells et al.

    Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity

    Behav. Brain Res.

    (2002)
  • G. Eichele

    Retinoids: from hindbrain patterning to Parkinson disease

    Trends Genet.

    (1997)
  • V. Enderlin et al.

    Age-related decreases in mRNA for brain nuclear receptors and target genes are reversed by retinoic acid treatment

    Neurosci. Lett.

    (1997)
  • N. Etchamendy et al.

    Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling.

    Behav. Brain Res.

    (2003)
  • A.A. Farooqui et al.

    Retinoic acid-mediated phospholipase A2 signaling in the nucleus

    Brain Res. Brain Res. Rev.

    (2004)
  • P. Fiorella et al.

    Expression of cellular retinoic acid-binding protein (type II) in Escherichia coli. Characterization and comparison to cellular retinoic acid-binding protein (type I)

    J. Biol. Chem.

    (1993)
  • F. Flood et al.

    Presenilin expression during induced differentiation of the human neuroblastoma SH-SY5Y cell line

    Neurochem. Int.

    (2004)
  • C. Folli et al.

    Ligand binding and structural analysis of a human putative cellular retinol-binding protein

    J. Biol. Chem.

    (2002)
  • B.M. Forman et al.

    Identification of a nuclear receptor that is activated by farnesol metabolites

    Cell

    (1995)
  • S.C. Fowler et al.

    Motor and associative deficits in D2 dopamine receptor knockout mice

    Int. J. Dev. Neurosci.

    (2002)
  • Z.Y. Gao et al.

    Retinoic acid induction of calcium channel expression in human NT2N neurons

    Biochem. Biophys. Res. Commun.

    (1998)
  • F.M. Harris et al.

    Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease

    J. Biol. Chem.

    (2004)
  • A. Heicklen-Klein et al.

    Tau promoter activity in neuronally differentiated P19 cells

    Brain Res.

    (2000)
  • E. Hermanson et al.

    Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells

    Exp. Cell Res.

    (2003)
  • T. Hirose et al.

    The orphan receptor Tak1 acts as a competitive repressor of RAR/RXR-mediated signaling pathways

    Biochem. Biophys. Res. Commun.

    (1995)
  • M. Husmann et al.

    Up-regulation of embryonic NCAM in an EC cell line by retinoic acid

    Dev. Biol.

    (1989)
  • M. Husson et al.

    Expression of neurogranin and neuromodulin is affected in the striatum of vitamin A-deprived rats

    Brain Res. Mol. Brain Res.

    (2004)
  • N. Idres et al.

    Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers

    J. Biol. Chem.

    (2002)
  • M.A. Iniguez et al.

    Characterization of the promoter region and flanking sequences of the neuron-specific gene RC3 (neurogranin)

    Brain Res. Mol. Brain Res.

    (1994)
  • D.G. Jacobs et al.

    Suicide, depression, and isotretinoin: is there a causal link?

    J. Am. Acad. Dermatol.

    (2001)
  • S. Jenab et al.

    Retinoic acid regulation of mu opioid receptor and c-fos mRNAs and AP-1 DNA binding in SH-SY5Y neuroblastoma cells

    Brain Res. Mol. Brain Res.

    (2002)
  • G. Kempermann et al.

    Functional significance of adult neurogenesis

    Curr. Opin. Neurobiol.

    (2004)
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