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Patterning of retinoic acid signaling and cell proliferation in the hippocampus.

ABSTRACT: The nuclear receptor ligand retinoic acid (RA) has been identified as an endogenous regulatory factor in the hippocampus, acting on pyramidal neurons and granule neuron progenitors, but almost nothing is known about the distribution of RA itself in the hippocampus. This study describes the source of RA for the rodent hippocampus in the meninges via the key RA synthetic enzyme retinaldehyde dehydrogenase 2 (RALDH2). Diffusion of RA from the meninges potentially creates a gradient of RA across the infrapyramidal and suprapyramidal blades of the dentate gyrus, enhanced by the expression of the RA catabolic enzyme Cyp26B1 between the blades, and an infrapyramidal and suprapyramidal blade difference is evident in RA-regulated transcription. This asymmetry may contribute to some of the physiological and molecular differences between the blades, including a disparity in the rates of cell proliferation in the subgranular zone of the two blades through RA inhibition of cell proliferation. Such differences can be altered by either the application of excess RA, its effect dependent on the relative position along the septotemporal axis, or change in RA signaling through mutation of retinol binding protein, while the capacity of RA to inhibit proliferation of cells in the dentate gyrus is demonstrated using in vitro slice culture. Use of synthetic and catabolic enzymes in the hippocampus to create differing zones of RA concentration parallels the mechanisms used in the developing brain to generate patterns of RA-regulated transcription.

SUBMITTER: Goodman T

PROVIDER: S-EPMC3505796 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Patterning of retinoic acid signaling and cell proliferation in the hippocampus.

Goodman Timothy T Crandall James E JE Nanescu Sonia E SE Quadro Loredana L Shearer Kirsty K Ross Alexander A McCaffery Peter P

Hippocampus 20120611 11

The nuclear receptor ligand retinoic acid (RA) has been identified as an endogenous regulatory factor in the hippocampus, acting on pyramidal neurons and granule neuron progenitors, but almost nothing is known about the distribution of RA itself in the hippocampus. This study describes the source of RA for the rodent hippocampus in the meninges via the key RA synthetic enzyme retinaldehyde dehydrogenase 2 (RALDH2). Diffusion of RA from the meninges potentially creates a gradient of RA across the ...[more]

PMID: 22689466

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Project description:BackgroundVitamin A is necessary for kidney development and has also been linked to regulation of solute and water homeostasis and to protection against kidney stone disease, infection, inflammation, and scarring. Most functions of vitamin A are mediated by its main active form, all-trans retinoic acid (tRA), which binds retinoic acid receptors (RARs) to modulate gene expression. We and others have recently reported that renal tRA/RAR activity is confined to the ureteric bud (UB) and collecting duct (CD) cell lineage, suggesting that endogenous tRA/RARs primarily act through regulating gene expression in these cells in embryonic and adult kidney, respectively.Methodology/principal findingsTo explore target genes of endogenous tRA/RARs, we employed the mIMCD-3 mouse inner medullary CD cell line, which is a model of CD principal cells and exhibits constitutive tRA/RAR activity as CD principal cells do in vivo. Combining antagonism of RARs, inhibition of tRA synthesis, exposure to exogenous tRA, and gene expression profiling techniques, we have identified 125 genes as candidate targets and validated 20 genes that were highly regulated (Dhrs3, Sprr1a, and Ppbp were the top three). Endogenous tRA/RARs were more important in maintaining, rather than suppressing, constitutive gene expression. Although many identified genes were expressed in UBs and/or CDs, their exact functions in this cell lineage are still poorly defined. Nevertheless, gene ontology analysis suggests that these genes are involved in kidney development, renal functioning, and regulation of tRA signaling.Conclusions/significanceA rigorous approach to defining target genes for endogenous tRA/RARs has been established. At the pan-genomic level, genes regulated by endogenous tRA/RARs in a CD cell line have been catalogued for the first time. Such a catalogue will guide further studies on molecular mediators of endogenous tRA/RARs during kidney development and in relation to renal defects associated with vitamin A deficiency.

Project description:Almost every organism has the ability of repairing damaged tissues or replacing lost and worn out body parts, nevertheless the degree of the response substantially differs between each species. Adult sea cucumbers from the Holothuria glaberrima species can eviscerate various organs and the intestinal system is the first one to regenerate. This process involves the formation of a blastema-like structure that derives from the torn mesentery edges by the intervention of specific cellular processes (e.g., cell dedifferentiation and division). Still, the genetic networks controlling the regenerative response in this model system are just starting to be unraveled. In this work we examined if and how the retinoic acid (RA) signaling pathway is involved in the regenerative response of this deuterostome. We first identified and characterized the holothurian orthologs for short chain dehydrogenase/reductase 7 (SDR7) and aldehyde dehydrogenase family 8A1 (ALDH8A1), two enzymes respectively associated with retinaldehyde and RA anabolism. We then showed that the SDR7 transcript was differentially expressed during specific stages of intestinal regeneration while ALDH8A1 did not show significant differences in regenerating tissues when compared to those of normal (non-eviscerated) organisms. Finally, we investigated the consequences of modulating RA signaling during intestinal regeneration using pharmacological tools. We showed that application of an inhibitor (citral) of the enzyme synthesizing RA or a retinoic acid receptor (RAR) antagonist (LE135) resulted in organisms with a significantly smaller intestinal rudiment when compared to those treated with DMSO (vehicle). The two inhibitors caused a reduction in cell division and cell dedifferentiation in the new regenerate when compared to organisms treated with DMSO. Results of treatment with tazarotene (an RAR agonist) were not significantly different from the control. Taken together, these results suggest that the RA signaling pathway is regulating the cellular processes that are crucial for intestinal regeneration to occur. Thus, RA might be playing a role in echinoderm regeneration that is similar to what has been described in other animal systems.

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Patterning of retinoic acid signaling and cell proliferation in the hippocampus.

Publications

Patterning of retinoic acid signaling and cell proliferation in the hippocampus.

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