Biomedical subjects

Ursula C Dräger

Publications and source records attributed to Ursula C Dräger.

7 recordsLinked to original sources

PubMed2006

Retinoic acid delineates the topography of neuronal plasticity in postnatal cerebral cortex.

Retinoic acid is well recognized to promote neuronal differentiation in the embryonic nervous system, but how it influences the postnatal cerebral cortex remains largely unknown. The domain of highest retinoic acid actions in the cortex of the mouse constricts postnatally to a narrow band that includes the dorsal visual stream and the attentional and executive networks. This band of cortex, which is distinguished by the retinoic acid-synthesizing enzyme RALDH3, exhibits signs of delayed maturation and enhanced plasticity compared to the surrounding cortex, as indicated by suppression of parvalbumin, neurofilament, cytochrome oxidase and perineuronal net maturation, and persistence of the embryonic, polysialated form of the neural cell-adhesion molecule PSA-NCAM. During the first postnatal week, the RALDH3-expressing territory translocates in the caudal cortex from the medial limbic lobe to the adjacent neocortex. This topographical shift requires the neurotrophin NT-3 because in mice lacking neuronal NT-3 the RALDH3 enzyme maintains its early postnatal pattern up to adulthood. In the NT-3-null mutants, expression of the markers, whose topography colocalizes with RALDH3 in the normal cortex, matches the abnormal RALDH3 pattern. This indicates that the uneven retinoic acid distribution serves a role in patterning the maturation and to some extent function of the normal postnatal cerebral cortex.

Aldehyde Oxidoreductases↗

PubMed2006

Retinoic acid signaling in the functioning brain.

Retinoic acid, an active form of vitamin A, regulates gene expression throughout the body, and many components of the signaling system through which it acts are present in the brain. Very little is known, however, about how retinoic acid functions in neurobiological systems. Several studies have provided evidence that retinoic acid plays a role in sleep, learning, and memory, but the precise mechanisms through which it influences these processes remain unclear. All of these processes involve local or long-range inhibition and synchronized neuronal activity between separate locations in the brain. A critical component in the generation of the synchronized firing of cortical neurons (cortical synchrony) is a network of inhibitory interneurons containing parvalbumin, a cell population affected by retinoid perturbations, such as exposure to a vitamin A overdose. An understanding of the role of retinoids in normal brain function would provide clues to the long-standing question of whether abnormalities in retinoic acid signaling contribute to the pathogenesis of some brain diseases with uncertain etiologies that involve both genetic and environmental factors.

Animals↗

PubMed2006

Retinoids, eye development, and maturation of visual function.

Vitamin A is known to be critical for the beginning of eye development as well as for photoreception in the functional retina. Hardly anything, however, is known about whether retinoic acid (RA)-regulated gene expression also plays a role in the long intervening period, during which the neurobiological retinal structure takes shape. The eye contains a highly intricate architecture of RA-synthesizing (RALDH) and degrading (CYP26) enzymes. Whereas the RALDHs are integrated in the early molecular mechanisms through which the dorso-ventral retina organization is established, the CYP26 enzymes are not necessary for this process and no molecular targets that match their retinal expression pattern have yet been identified. In this article we describe that CYP26 expression in the mouse is most distinctive during later stages of retina formation. Throughout development CYP26A1 degrades RA in a horizontal region that extends across the retina, but during later embryonic and postnatal retina maturation this function is reinforced by another enzyme, CYP26C1. RA applications at this stage do not affect the RALDHs but cause differential changes in CYP26 expression: Cyp26a1 is up-regulated, but more rapidly by 9-cis than all-trans RA, Cyp26c1 is down-regulated, and Cyp26b1, which is undetectable in the normal mouse retina, is strongly activated in retinal ganglion cells. The dynamic regulation in RA-difference patterns by the CYP26 enzymes may set up spatial constellations for expression of genes involved in formation of retinal specializations for higher acuity vision, which are known to form over a prolonged period late in retina development.

Aldehyde Oxidoreductases↗

PubMed2004

A retinoic-acid critical period in the early postnatal mouse brain.

BACKGROUND: A normal supply of vitamin A, which regulates gene expression through its active form retinoic acid, is required by many organs; both excess and deficiency can be teratogenic. Very little is known about the role of retinoic acid in maturation of the mammalian forebrain. METHODS: As retinoic acid cannot be visualized directly, we mapped its actions in the forebrain with indirect morphologic methods and by applying retinoic acid overdoses to early postnatal mice. RESULTS: During this time, the morphologic indicators of retinoic acid actions are localized mainly in the limbic system and they undergo rapid changes. Retinoic acid overdoses can cause lasting behavioral abnormalities that point to disrupted limbic functions. In the anterior cingulate cortex, inhibitory interneurons are affected, and in the hippocampus, primarily the dentate gyrus is abnormal. CONCLUSIONS: Retinoic acid is involved in functional maturation of limbic regions of the forebrain with a critical stage early postnatally in mice, when their brains are particularly vulnerable to vitamin A perturbations. This developmental time in mice compares with the second trimester of gestation in humans, a stage when in genetically predisposed individuals the corresponding brain regions are known to pass through a period of increased susceptibility to environmental disturbances.

Age Factors↗

PubMed2004

CYP26A1 and CYP26C1 cooperate in degrading retinoic acid within the equatorial retina during later eye development.

In the embryonic mouse retina, retinoic acid (RA) is unevenly distributed along the dorsoventral axis: RA-rich zones in dorsal and ventral retina are separated by a horizontal RA-poor stripe that contains the RA-inactivating enzyme CYP26A1. To explore the developmental role of this arrangement, we studied formation of the retina and its projections in Cyp26a1 null-mutant mice. Expression of several dorsoventral markers was not affected, indicating that CYP26A1 is not required for establishing the dorsoventral retina axis. Analysis of the mutation on a RA-reporter mouse background confirmed, as expected, that the RA-poor stripe was missing in the retina and its projections at the time when the optic axons first grow over the diencephalon. A day later, however, a gap appeared both in retina and retinofugal projections. As explanation, we found that CYP26C1, another RA-degrading enzyme, had emerged centrally in a narrower domain within the RA-poor stripe. While RA applications increased retinal Cyp26a1 expression, they slightly reduced Cyp26c1. These observations indicate that the two enzymes function independently. The safeguard of the RA-poor stripe by two distinct enzymes during later development points to a role in maturation of a significant functional feature like an area of higher visual acuity that develops at its location.

Animals↗

PubMed2004

Retinoic acid signaling in the brain marks formation of optic projections, maturation of the dorsal telencephalon, and function of limbic sites.

As retinoic acid (RA) is known to regulate the expression of many neuronal proteins, it is likely to influence overall development and function of the brain; few particulars, however, are available about its role in neurobiological contexts due mainly to problems in RA detection. To ask whether the function of RA in the rostral brain is concentrated in particular neurobiological systems, we compared sites of RA synthesis and actions, as detected by RA signaling in reporter mice, for embryonic and adult ages. We found that most sites of RA actions in the forebrain do not colocalize with RA synthesis, consistent with a dominant RA supply by diffusion and the circulation. The changing RA patterns distinguish preferentially two complex functional schemes. (1) Within the visual system when the first optic axons grow toward their targets, RA signaling delineates the topographical adjustment of the retinal map, which is encoded in the coordinates of the visual world, to central visual maps, which are formed in the segmental brain coordinates. (2) The second scheme begins early in forebrain morphogenesis as a distinction of the dorsal telencephalon. With progressing development, and in the adult, the RA patterns then focus on widely distributed structures, most of which belong to the limbic system. These are sites in which emotional perception is combined with higher cognitive processes and in which normal function requires ongoing remodeling of synaptic connections, indicating that the developmental role of RA in promotion of neuronal differentiation programs continues in the adult brain for highly flexible neural circuits. J. Comp. Neurol. 470:297-316, 2004.

Animals↗

PubMed2002

Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems.

Retinoic acid (RA) affects development and function of the brain, but little is known about how much is made locally and where it is distributed. To identify RA-sensitive neural processes, we mapped the RA-synthesizing retinaldehyde dehydrogenases (RALDHs) during postnatal brain formation of the mouse. High and stable RALDH expressions mark the basal ganglia, olfactory bulbs, hippocampus and auditory afferents as major sites of RA actions in the functional brain. During the early postnatal period, transient and very high RALDH3 expressions distinguish two developmental events: (i) the colonization of the nucleus accumbens and the olfactory bulbs by neuronal precursors and (ii) the maturation of selected parts of the cerebral cortex. In the cortex, RALDH3 is transiently activated in postmigratory layer II/III neurons during formation of their dendritic arbors and it is transported in their axons across the corpus callosum. RALDH3-expressing cortical regions include most of the limbic lobe, with strongest expression in the anterior cingulate cortex, medial and lateral secondary visual cortices, auditory cortical areas, the secondary motor cortex and some association areas. The transient cortical expression points to a brief RA-critical period during differentiation of the cortical network that serves in the coordination of sensory-motor activity with emotional and recently learned information.

Aldehyde Oxidoreductases↗