Patterning of retinoic acid signaling and cell proliferation in the hippocampus.
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.
Institute of Medical Sciences, University of Aberdeen, Aberdeenshire, United Kingdom.
Timothy
T
Goodman
James E
JE
Crandall
Sonia E
SE
Nanescu
Loredana
L
Quadro
Kirsty
K
Shearer
Alexander
A
Ross
Peter
P
McCaffery
D000080924:Aldehyde Dehydrogenase 1 Family; D000445:Aldehyde Oxidoreductases / Q000032:analysis*; D000818:Animals; D002455:Cell Division; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D018891:Dentate Gyrus / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology / Q000648:ultrastructure; D017930:Genes, Reporter; D007527:Isoenzymes / Q000032:analysis*; D008578:Meninges / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D050697:Retinal Dehydrogenase / Q000032:analysis*; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000032:analysis / Q000502:physiology*
D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607081:Cyp26b1 protein, mouse; C000607082:Cyp26b1 protein, rat; D000072516:Retinoic Acid 4-Hydroxylase; D000445:Aldehyde Oxidoreductases; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; C523119:Aldh1a1 protein, rat; C470579:RALDH2 protein, mouse; D050697:Retinal Dehydrogenase