E. Kennedy Shriver Center, Waltham, MA 02452, University of Massachusetts Medical School, Worcester, MA and Harvard Medical School, Boston, MA, USA
Address correspondence to Ursula C. Dräger, E. Kennedy Shriver Center, Waltham, MA 02452, USA. Email: ursula.drager{at}umassmed.edu.
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Abstract |
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Introduction |
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The early brain is completely devoid of RA synthesis, but is flanked by two regions of extremely high RALDH expression, one located rostrally in the eye and face, the other caudally in the trunk (Smith et al., 2001; Niederreither et al., 2002
). Many different lines of evidence indicate that the morphogenesis of the early hindbrain depends on an RA gradient that emanates from the RALDH-rich trunk (Gavalas and Krumlauf, 2000
) and RA diffusing from the eye and face influences the early fore-brain (Enwright and Grainger, 2000
). As the embryonic brain grows, most neuronal tissue remains free of RA synthesis, but RALDH expression moves closer: RALDH3 begins to be expressed centrally within the embryonic telencephalon in the lateral ganglionic eminence and RALDH2 appears externally in the meninges (Smith et al., 2001
). Comparisons of RALDH expressions at different locations in the developing embryo show that levels are very high at sites and during periods of neurogenesis and neuronal differentiation, but decline with maturation (McCaffery et al., 1993
; McCaffery and Dräger, 1994a
,b
). This is consistent with a role of RA in neuronal determination and promotion of neurite outgrowth.
Recent observations indicate that retinoid-dependent processes are also essential for several functions in the adult brain: RA is required for formation of new song neurons in male finches (Denisenko-Nehrbass et al., 2000), normal motor performance is controlled by RA receptors expressed in the basal ganglia (Krezel et al., 1998
) and the presence of RA receptors and RA is necessary for the cellular mechanisms that underlie learning and memory in the hippocampus (Chiang et al., 1998
; Misner et al., 2001
). RA receptors and retinoid-binding proteins continue to be expressed throughout the adult brain in characteristic and overlapping patterns (Krezel et al., 1999
). However, reports on how much RA is made in the brain and where it is localized, are contradictory. Traditionally, the brain was not included in RA measurements, because its RA content was believed to be negligible (Napoli, 1994
). More recently, traces of RA synthesis (Zetterstrom et al., 1999
) or low levels were detected in the adult brain (Connor and Sidell, 1997
; Zetterstrom et al., 1999
). General synthesis was described to be very high, twice the rate as in the retinoid-rich liver (Dev et al., 1993
), or robust synthesis was localized selectively to the hippocampus (Misner et al., 2001
). The total RA content was reported to be derived largely from the circulation (Kurlandsky et al., 1995
), or, under different conditions, it was found to be synthesized almost exclusively locally within the brain (Werner and Deluca, 2002
). These divergent conclusions reflect the particular measurement techniques, because RA cannot be fixed and visualized directly, and because the trace lipid RA is difficult to detect by HPLC in the lipid-rich brain.
As the RALDHs are critical determinants for the sites of RA actions, their expression sites provide the best available histological criteria to estimate RA distribution. Localization of the mRNAs gives only a partial view for the brain, because neurons can transport functional RALDH enzymes axonally across long distances. Here, we used a combination of several techniques to localize the sites of RA synthesis in the postnatal brain. We will first describe the stable RALDH expression in the adult brain and then transient RALDH3 patterns during early postnatal brain maturation. The RALDH patterns we observed show intriguing spatial and temporal parallels to subtle neuroanatomical abnormalities described in schizophrenia (Lewis and Lieberman, 2000; Sawa and Snyder, 2002
), an illness which has previously been connected with the retinoid system (Goodman, 1998
). Schizophrenia, a severe mental disorder of unknown etiology, is commonly believed to be of neurodevelopmental origin and due both to genetic and environmental factors. The subtle neuroanatomical abnormalities in schizophrenic brains, which are most pronounced in regions involved in the integration of sensory-motor functions with cognition, drive and emotion, show signs of impaired neuronal differentiation (Selemon and Goldman-Rakic, 1999
). In a separate article, we explain how the sites and developmental stages of RA actions described here fit together with well-established knowledge from the retinoid field to provide a hypothetical pathophysiological mechanism for schizophrenia (U.C. Dräger et al., manuscript under revision).
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Materials and Methods |
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Results |
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RALDH2
In the embryo, all RALDH2 expression in the forebrain is limited to the meninges, and neuronal expression is seen only in a few neurons of the hindbrain and spinal cord (Zhao et al., 1996; Niederreither et al., 1997
; Smith et al., 2001
). A similar pattern continues throughout postnatal development into the adult: all RALDH2 expression in the rostral postnatal brain is located in meninges and only in the medulla can a few neurons be detected (not shown). The distribution of RALDH2 protein in the rostral brain is shown on coronal sections through different levels of the hippocampus, viewed at low and higher magnifications, to illustrate a meningeal specialization (Fig. 1ae
): RALDH2 is strongly expressed in the remnants of the meninges, which covered the outer telencephalic surface in the embryo and which condensed into evenly spaced channel-like structures (arrows), as the medial telencephalic rim curled inwards to form the hippocampus. In the more rostral sections (Fig. 1a,c,d
), the meningeal channels are cut perpendicular and the caudal section (Fig. 1b,e
) gives a tangential view.
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Neuronal RALDH1 expression in the embryonic brain is restricted to dopaminergic cells in the ventral tegmentum, which project to the forebrain, and minor levels are detected prenatally in the meninges (McCaffery and Dräger, 1994; Smith et al., 2001). These two RALDH1 sites remain similar in the adult brain, but the expression levels increase dramatically: a rather small number of neurons in the ventral midbrain (Fig. 1h,i
) send vast amounts of RALDH1 enzyme by axonal transport to the ventral telencephalon, the dorsal striatum (Fig. 1f,g
) and the nucleus accumbens shell. During the first postnatal week, a few of the RALDH1-labeled axons can be seen to stray also into the dorsal telencephalon, mainly medio-rostrally into the cingulate cortex; at later stages, aberrant fibers are no longer detectable (not shown). These transient misprojections are minor and are likely an example of exuberant early projections. RALDH1 is also strongly expressed in the adult meninges, in particular in the RALDH2-positive channels that surround the hippocampus (Fig. 1h,j
). In addition, the blood vessels of the entire brain appear labeled by the RALDH1 antiserum. Because tissue edges, like blood vessels and meninges, are notorious for histological artifacts, we compared dissected samples for RALDH expressions by Northern blotting (Fig. 2a
): the outer cortex preparation, which consisted of upper cortical layers and meninges, contains both high RALDH1 and RALDH2 levels, and the lower cortical layers have only RALDH1. Isolated hippocampi express RALDH2 and very high RALDH1 mRNA levels. The RALDH1 mRNA comes in two transcript sizes: the blood vessels and meninges of the adult brain contain a heavier band (
2.5 kb) and a lighter band (
2 kb) is expressed at all other locations, including embryonic retina and brain, adult retina, substantia nigra, liver and kidney (Smith et al., 2001
).
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RALDH3 expression is overall very low in the adult forebrain: it is not detectable in adult dorsal telencephalon, either by Northern blotting (Fig. 2) or histological screens. A small number of neurons in the ventral telencephalon and the hypothalamus contain RALDH3 protein (not shown). By far the strongest forebrain expression is in the olfactory bulbs (Fig. 1k,m
): a subpopulation of periglomerular cells expresses high amounts of RALDH3 enzyme throughout their cell bodies and dense processes that fill the glomeruli diffusely. Double-labeling for tyrosine hydroxylase (TH) shows that the RALDH3-containing periglomerular cells are distinct from the dopaminergic interneurons (Fig. 1mo
). The small somata of the periglomerular cells can also be detected by in situ hybridizations for RALDH3 mRNA (not shown). In addition to the high RALDH3 expression, the adult olfactory bulb is surrounded by RALDH1- and RALDH2-positive meninges that follow the olfactory nerve fibers for some distance into its ventral side, as illustrated in Figure 1l
for a parasagittal RALDH2-labeled section. These combined RALDH expressions make the olfactory bulbs, next to the striatum, the RA-richest parts of the adult forebrain.
Compared to the overall sparse RALDH3 expression in the adult forebrain, very high levels are detectable in the hindbrain: the cochlear nucleus appears almost solidly labeled by the RALDH3 antiserum (Fig. 3g). When we tested the same region by Northern blotting and in situ hybridization, however, practically no RALDH3 mRNA was found to be present in the cochlear nucleus itself, although mRNA could be detected nearby in large RALDH3-positive neurons of the facial nucleus (Fig. 3d
and not shown). In order to determine the origin of the RALDH3 enzyme in the cochlear nucleus, we tested the inner ear; for technical reasons, we sectioned early postnatal heads, when the skull was not yet ossified. In situ hybridizations show very strong RALDH3 mRNA expression in the somata of the spiral-ganglion neuron within the cochlea (Fig. 3a
). Immunohisto-chemical preparations indicate that RALDH3 enzyme is transported along the peripheral axonal branches towards the auditory hair cells (Fig. 3c
) and in the centrifugal branches along the auditory nerve towards the cochlear nucleus (Figs. 3b,f
).
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Ventral Telencephalon
During embryonic forebrain development, RALDH3 is strongly expressed in the ventral telencephalon and it represents a major local RA source at early stages. In the later embryo, RALDH3 mRNA levels decline, as is apparent on entire telencephala of different ages tested by Northern blotting (Smith et al., 2001). When such assays are extended to postnatal ages (Fig. 2b
), the total amounts of telencephalic RALDH3 mRNA can be seen to rise again transiently during the first postnatal week and then to decline slowly to undetectable adult levels. In order to find out where this transient RALDH3 expression is located, we screened postnatal brains of different ages by in situ hybridization and immunohistochemistry. For the ventral telencephalon, Figure 4c,e
gives the localization of RALDH3 mRNA at postnatal day 1.5 (P1.5), and Figure 4d,f
shows RALDH3 protein in adjacent sections. As in the late embryo (Fig. 4a,b
), RALDH3 mRNA in the early postnatal brain is located mostly in the rostral subventricular zone (SVZ) of the lateral ventricles, but only small amounts remain. The neighboring antiserum-labeled sections (Fig. 4d,f
) indicate that high RALDH3-protein expression persists in small cells that appear to move. Figure 4gm
illustrates RALDH3-labeled cells in continuity with the SVZ during early postnatal days: some seem to disperse along the SVZ (Fig. 4g
), some head towards the septum and the nucleus accumbens (Fig. 4h,i
) and others head towards the olfactory bulb via the rostral migratory stream (Fig. 4km
). While RALDH3-labeled cells in the septum and in the olfactory tubercle (Fig. 4j
) exhibit already differentiated neuronal features, most of the streaming cells are tiny, consisting mainly of a stubby process with large growth cone and tight perisomal region. This is shown in Figure 4m
for a cell that seems to have made a right-angle turn from the rostral migratory stream, located centrally in the olfactory bulb, towards the glomerular layer. Such RALDH3-labeled cells are most common during the first postnatal week, but a few much more weakly labeled ones can be found in the adult olfactory bulb.
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While RALDH3 mRNA declines in the ventral telencephalon, it increases dorsally in parts of the cerebral cortex. The locations and the rising phase of the cortical expression are shown on low-power coronal brain sections for different ages reacted by in situ hybridization (Fig. 5). In the embryonic dorsal telencephalon, no RALDH3 can be detected (Fig. 4a,b
), but all expression seems to begin after birth. At P1.5, the cortical expression is still weak; it increases over the following few days up to a maximum around P6; by P10 levels have declined again significantly and by P13 only remnants remain visible. The labeled regions form one continuous band that extends along the medial cortex and wraps around the occipital pole; a second continuous region is labeled in the lateral part of the caudal telencephalon, adjoining the rhinal fissure (arrows). Both the lateral and particularly the medial parts are much larger than single cytoarchitectonic areas. As judged by their locations, the labeled regions include both limbic and neocortical areas. A tentative list of the medial areas, using a simplified version of Paxinos and Franklins (Paxinos and Franklin, 2001
) nomenclature for the adult mouse, includes the following limbic areas: piriform cortex, medial orbital cortex, prelimbic cortex, cingulate cortical areas, retrosplenial cortices and presubiculum; as well as the following neocortical areas: parietal association cortices, secondary motor area and medial secondary visual area. The caudo-temporal areas include the lateral secondary visual area, the secondary and primary auditory areas, the temporal association cortex and the ectorhinal cortex. Neither by in situ hybridization nor by Northern blotting did we detect RALDH3 mRNA in the hippocampus. The labeling intensity changes over time, both absolutely and relatively. Along the medial band, intensity steps are apparent and become more abrupt with time. Although these appear to demarcate future cytoarchitectonic boundaries, the labeling intensity does not distinguish limbic from neocortical areas: it is strongest in the anterior cingulate cortex (ACC) and more rostral limbic areas, as well as in the parietal association cortex (PtA) and the medial secondary visual area (V2M).
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Discussion |
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We have described here the localizations of three major RA-generating dehydrogenases in the postnatal brain. Of the three, RALDH2 and RALDH3 are highly efficient in RA production, whereas RALDH1 is much less so per amount of protein. RALDH1 occurs at very high protein concentrations, however, and it has been described to function in addition as binding protein for small lipophilic compounds, including thyroid (Yamauchi and Tata, 1994) and steroid hormones (Pereira et al., 1991
). The three RALDHs are likely to represent the main local sources of RA for the brain, as we did not detect any other major enzymes in previous biochemical assays (McCaffery and Dräger, 1995
). By such assays several aldehyde/xanthine-oxidase activities are observed at different locations throughout the body, but their contributions to total RA synthesis appear to be relatively minor (Manthey et al., 1990
). We do not have evidence for the expression of major novel RALDHs, as were recently postulated for the early embryo (Mic et al., 2002
). As in the embryonic brain (Smith et al., 2001
), we find only rather sparse RALDH expression postnatally. Our observations are consistent with the measurements by Kurlandski et al. (Kurlandsky et al., 1995
) on the origins of tissue RA pools in the adult rat: they reported that almost 90% of total brain RA is not synthesized locally but is taken up from the plasma RA pool. Similarly, Le Doze et al. (Le Doze et al., 2000
) found that intravenously injected all-trans-RA permeates into the brain white matter to concentrations six or seven times higher than those of the serum. It seems thus plausible that the RA concentrations in large parts of the brain represent a partition equilibrium between lipophilic pockets on serum proteins and the lipid-rich brain. In selected locations close to RALDHs, however, local RA levels must be significantly higher than average brain levels.
In a study on vitamin-A-deprived rats, Werner and Deluca (Werner and Deluca, 2002) observed that a large fraction of a systemically injected retinol dose is converted locally within the brain into RA and that RA is not preferentially imported from the plasma; they conclude that the brain synthesizes RA more efficiently than other tissues. One interpretation of this result, which differs from the observations in vitamin-A-sufficient rats, is that the brain might be a privileged site of retinol uptake from the circulation under conditions of severe vitamin-A deficiency. By electrophysiological analyses, Chiang, Misner and colleagues established that RA actions are absolutely required for the mechanisms of learning and memory in the adult hippocampus (Chiang et al., 1998
; Misner et al., 2001
); their observations characterize the hippocampus as a major site of RA usage in the brain. To account for local RA synthesis, we found expression of both RALDH1 and RALDH2 in the meninges and particularly the meningeal channels surrounding the hippocampus; RALDH1 is expressed in addition in the blood vessels (Fig. 1
). In previous biochemical assays on RA-synthesizing enzymes in the adult hippocampus (McCaffery and Dräger, 1994a
), we detected only RALDH2 activity. However, for technical reasons additional RA synthesis by RALDH1 cannot be excluded, because RALDH1 function tends to become undetectable in dilute samples due to its high oxidation vulnerability. Alternatively, it is possible that the enzyme translated from the heavier RALDH1 mRNA transcript, which is expressed selectively in adult meninges and blood vessels, differs from the more common product of the lower mRNA band, on which all previous functional RALDH1 assays were done (McCaffery et al., 1992
; McCaffery and Dräger, 1994). For instance, it might be that the lipophilic binding properties mentioned above (Pereira et al., 1991
; Yamauchi and Tata, 1994
) are relatively more pronounced compared to RA synthesis in the heavier than the lower-band product, and that RALDH1 contributes to accumulation of retinol from the circulation into the brain.
Although most of our analyses were focused on the rostral brain, we illustrate in Figure 3 the axonal transport of RALDH3 protein from the inner ear to the brain stem. This situation is a parallel to the nigro-striatal RALDH1 projection, where all RALDH1 mRNA is confined to the ventral tegmentum and practically all of the functional enzyme is transported axonally to the ventral telencephalon (McCaffery and Dräger, 1994; Smith et al., 2001
). The function of RALDH3 transport from the spiral ganglion might be a trophic influence of the inner ear on the cochlear nucleus. The tegmental projection onto the striatum is well known to exert a strong trophic influence. This influence is commonly ascribed to dopamine, but RA synthesis might be a significant additional component; the RALDH1 inhibitor disulfiram (Antabuse) is known to cause acute Parkinsons disease in rare instances (Laplane et al., 1992
).
Transient RALDH expression events are likely to mark critical periods of RA actions, as defined by Shenefelt (Shenefelt, 1972). This is the case for the earliest expression in the prospective forebrain: RALDH2 appears for a few hours during the start of neurulation at the rostral edge of the neural plate, where the eyes and telencephalon will develop (Wagner et al., 2000
; Smith et al., 2001
). This event marks the most teratogenic period for the eyes and brain, because an excess of RA just prior to and during the start of RALDH2 expression causes the most severe malformations (Shenefelt, 1972
). The transient RALDH3 expression in migrating precursors of the newborn ventral telencephalon undoubtedly represents the postnatal tail of the neuronal migration from the remnants of the embryonic lateral ganglionic eminence. It seems plausible that the tiny migrating cells turn down RALDH3 transcription for economic reasons, while on route. The origin, path and final phenotype of precursors migrating out from the ganglionic eminence have been beautifully illustrated by grafting labeled cells into the early embryo (Wichterle et al., 2001
): lateral-ganglionic-eminence-derived cells migrate antero-ventrally to transform into distinct neuronal populations in the striatum, nucleus accumbens, olfactory tubercle and olfactory bulb.
The transient expression of RALDH3 in an odd assortment of cortical areas clearly does not demarcate similar cytoarchitectonic areas nor neoversus allocortex, but it appears to distinguish a network of cortical circuits that connects peristriate visual areas with other cortical regions (Vogt and Miller, 1983). RALDH3 appears in early postmigratory neurons and it accompanies their major period of dendritic arborization. Although neurogenesis is complete by E17 in the mouse, the medial cortex is last to mature (Caviness et al., 2000
), which makes it likely that new neurons continue to arrive through the first part of RALDH3 expression. The RALDH3-labeled cells are the youngest subpopulation of the entire callosal projection, which originates in addition to layers II/III from layer V and the subplate (DeAzevedo et al., 1997
). The labeled cortical areas represent a system involved in the integration of sensorimotor circuits with emotional and remembered information (Vogt and Miller, 1983
). In particular, the anterior cingulate cortex is now considered as the cortical center where perception is linked with motor control to provide a network for motivation, cognition, intelligent behavior and emotional self-control in humans (Paus, 2001
). It is intriguing to find that RALDH3, which is the most important RA source for the embryonic retina, also marks the differentiation stage of the cortical system for visual working memory and cognitive functions. This cortical network is evolved to much higher sophistication in primates, whose visual capacity also dramatically exceeds that of mice. It may be that higher mental functions evolved as a corollary of higher visual capacity, since logical reasoning, in the absence of any visual input, was found to activate an occipitoparietalfrontal network in humans (Knauff et al., 2002
), which includes the areas homologous to the RALDH3-labeled cortex in the mouse.
The sites of RALDH3 expression in the mouse represent the cortical regions that correspond to areas in the human brain which are disproportionately affected in schizophrenia and mood disorders, and the corresponding developmental stage is during the second trimester, which is also a vulnerable period for the acquisition of a schizophrenia predisposition (DeAzevedo et al., 1997; Lewis and Lieberman, 2000
; Pearlson, 2000
; Sawa and Snyder, 2002
). This lead will be pursued ielsewhere (U.C. Dräger et al., manuscript under revision).
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Footnotes |
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We thank F. Grün for his contributions to the generation of the new RALDH3 antiserum, R. Lindahl for the RALDH1 antiserum, J. Crandall and other members of the E.K. Shriver Center for help and comments, and J. Adams, F. Benes, W. Blaner and U. Hämmerling for discussions. This work was supported by NIH grant EY01938.
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References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Caviness VS, Takahashi T, Nowakowski RS (2000) Neocortical malformation as consequence of nonadaptive regulation of neuronogenetic sequence. MRDD Res Rev 6:2233.
Chiang MY, Misner D, Kempermann G, Schikorski T, Giguere V, Sucov HM, Gage FH, Stevens CF, Evans RM (1998) An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. Neuron 21:13531361.[ISI][Medline]
Connor MJ, Sidell N (1997) Retinoic acid synthesis in normal and Alzheimer diseased brain and human neural cells. Mol Chem Neuropathol 30:239252.[ISI][Medline]
DeAzevedo LC, Hedin-Peirera C, Lent R (1997) Callosal neurons in the cingulate cortical plate and subplate of human fetuses. J Comp Neurol 386:6070.[ISI][Medline]
Denisenko-Nehrbass NI, Jarvis E, Scharff C, Nottebohm F, Mello CV (2000) Site-specific retinoic acid production in the brains of adult song birds. Neuron 27:359370.[ISI][Medline]
Dev S, Adler A, Edwards R (1993) Adult rabbit brain synthesizes retinoic acid. Brain Res 632:14.[ISI][Medline]
Enwright JF, Grainger RM (2000) Altered retinoid signaling in the heads of Small eye mutant mouse embryos. Dev Biol 221:122.[ISI][Medline]
Gavalas A, Krumlauf R (2000) Retinoid signaling and hindbrain patterning. Curr Opin Genet Dev 10:380386.[ISI][Medline]
Goodman AB (1998) Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 95: 72407244.
Knauff M, Mulack T, Kassubek J, Salih HR, Greenlee MW (2002) Spatial imagery in deductive reasoning: a functional MRI study. Brain Res Cogn Brain Res 13:203212.[ISI][Medline]
Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrell IE, Chambon P (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279:863867.
Krezel W, Kastner P, Chambon P (1999) Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience 89:12911300.[ISI][Medline]
Kurlandsky SB, Gamble MV, Ramakrishnan R, Blaner WS (1995) Plasma delivery of retinoic acid to tissues in the rat. J Biol Chem 270:1785017857.
Laplane D, Attal N, Sauron B, de Billy A, Dubois B (1992) Lesions of basal ganglia due to disulfiram neurotoxicity. J Neurol Neurosurg Psychiatry 55:925929.[Abstract]
Le Doze F, Debruyne D, Albessard F, Barre L, Defer GL (2000) Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of rat. Drug Metab Dispos 28: 205208.
Lewis DA, Lieberman JA (2000) Catching up on schizophrenia: natural history and neurobiology. Neuron 28:325334.[ISI][Medline]
McCaffery P, Dräger UC (1994a) High levels of a retinoic-acid generating dehydrogenase in the meso-telencephalic dopamine system. Proc Natl Acad Sci USA 91:77727776.[Abstract]
McCaffery P, Dräger UC (1994b) Hotspots of retinoic acid synthesis in the developing spinal cord. Proc Natl Acad Sci USA 91:71947197.[Abstract]
McCaffery P, Dräger UC (1995) Retinoic acid synthesizing enzymes in the embryonic and adult vertebrate. Adv Exp Med Biol 372:173183.[Medline]
McCaffery P, Lee M-O, Wagner MA, Sladek NE, Dräger UC (1992) Asymmetrical retinoic acid synthesis in the dorso-ventral axis of the retina. Development 115:371382.[Abstract]
McCaffery P, Posch KC, Napoli JL, Gudas L, Dräger UC (1993) Changing patterns of the retinoic acid system in the developing retina. Dev Biol 158:390399.[ISI][Medline]
Mangelsdorf DJ, Umesono K, Evans RM (1994) The retinoid receptors. In: The retinoids: biology, chemistry, and medicine (Sporn MB, Roberts AB, Goodman DS, eds), pp. 319349. New York: Raven Press.
Manthey CL, Landkamer GJ, Sladek NE (1990) Identification of the mouse aldehyde dehydrogenases important in aldophosphamide detoxification. Cancer Res 50:49915002.[Abstract]
Mark M, Ghyselinck NB, Wendling O, Dupe V, Mascrez B, Kastner P, Chambon P (1999) A genetic dissection of the retinoid signalling pathway in the mouse. Proc Nutr Soc 58:609613.[ISI][Medline]
Mic FA, Haselbeck RJ, Cuenca AE, Duester G (2002) Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development 129:22712282.
Misner DL, Jacobs S, Shimizu Y, de Urquiza AM, Solomin L, Perlman T, De Luca LM, Stevens CF, Evans RM (2001) Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Proc Natl Acad Sci USA 98:1171411719.
Napoli JL (1994) Retinoic acid homeostasis. Prospective roles of betacarotene, retinol, CRBP, and CRABP. In: Vitamin A in health and disease (Blomhoff R, ed.), pp. 135188. New York: Marcel Dekker.
Niederreither K, Fraulob V, Garnier J-M, Chambon P, Dollé P (2002) Differential expression of retinoic acid-synthesizing (RALDH) enzymes during fetal development and organ differentiation in the mouse. Mech Dev 110:165171.[ISI][Medline]
Niederreither K, McCaffery P, Dräger UC, Chambon P, Dollé P (1997) Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech Dev 62:6778.[ISI][Medline]
Paus T (2001) Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nature Reviews 2:417424.[ISI][Medline]
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. New York: Academic Press.
Pearlson GD (2000) Neurobiology of schizophrenia. Ann Neurol 48:556566.[ISI][Medline]
Pereira F, Rosenmann E, Nylen E, Kaufman M, Pinsky L, Wrogemann K (1991) The 56 kDa androgen binding protein is an aldehyde dehydrogenase. Biochem Biophys Res Commun 175:831838.[ISI][Medline]
Sawa A, Snyder SH (2002). Schizophrenia: diverse approaches to a complex disease. Science 296:692695.
Selemon LD, Goldman-Rakic PS (1999) The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45:1725.[ISI][Medline]
Shenefelt RE (1972) Morphogenesis of malformations in hamsters caused by retinoic acid. Teratology 5:403418.
Smith D, Wagner E, Koul O, McCaffery P, Dräger UC (2001) Retinoic acid synthesis for the developing telencephalon. Cereb Cortex 11: 894905.
Vogt BA, Miller MW (1983) Cortical connections between rat cingulate cortex and visual, motor and postsubicular cortices. J Comp Neurol 216:192210.[ISI][Medline]
Wagner E, McCaffery P, Dräger UC (2000) Retinoic acid in the formation of the dorso-ventral retina and its central projections. Dev Biol 222: 460470.[ISI][Medline]
Werner EA, Deluca HF (2002) Retinoic acid is detected at relatively high levels in the CNS of adult rats. Am J Physiol Endocrinol Metab 282:E672E678.
Wichterle H, Turnbull DH, Nery S, Fishell G, Alvarez-Buylla A (2001) In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. Development 128:37593771.
Yamauchi K, Tata JR (1994) Purification and characterization of a cytosolic thyroid-hormone-binding protein (CTBP) in Xenopus liver. Eur J Biochem 225:11051112.[Abstract]
Zetterstrom RH, Lindquist E, Mata de Urquiza A, Tomac A, Eriksson U, Perlmann T, Olson L (1999) Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci 11:407416.[ISI][Medline]
Zhao D, McCaffery P, Ivins KJ, Neve RL, Hogan P, Chin WW, Dräger UC (1996) Molecular identification of a major retinoic-acid synthesizing enzyme: a retinaldehyde-specific dehydrogenase. Eur J Biochem 240:1522.[Abstract]