title: Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.
abstract: Retinoic acid (RA) is a potent regulator of gene transcription via its activation of a set of nuclear receptors controlling transcriptional activation. Precise maintenance of where and when RA is generated is essential and achieved by local expression of synthetic and catabolic enzymes. The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression, crucial for morphogenesis. This paracrine role of RA has been assumed to occur in most tissues and that the RA synthetic enzymes release RA at a site distant from the catabolic enzymes. In contrast to the embryonic CNS, relatively little is known about RA metabolism in the adult brain. This study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. In vivo use of a new and potent inhibitor of the Cyp26 enzymes, ser 2-7, demonstrated a function for endogenous Cyp26 in the brain and that hippocampal RA levels can be raised by ser 2-7, altering the effect of RA on differential patterning of cell proliferation in the hippocampal region of neurogenesis, the subgranular zone. The expression of CYP26A1 and CYP26B1 was also investigated in the adult human brain and colocalization of CYP26A1 and the RA synthetic enzyme RALDH2 indicated a different, autocrine role for RA in human hippocampal neurons. Studies with the SH-SY5Y human neuroblastoma cell line implied that the co-expression of RA synthetic and catabolic enzymes maintains retinoid homeostasis within neurons. This presents a novel view of RA in human neurons as part of an autocrine, intracellular signaling system.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Stoney
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.|Department of Neurology, Universidade Metropolitana de Santos, Santos, SP, Brazil.
authors.forename: Yara D
authors.initials: YD
authors.lastname: Fragoso
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Reem Bu
authors.initials: RB
authors.lastname: Saeed
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Ashton
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Goodman
authors.affiliation: Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
authors.affiliation: Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.|Pharmaceutical Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Gomaa
authors.affiliation: Department of Physiopathology, Universidade Metropolitana de Santos, Santos, SP, Brazil.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sementilli
authors.affiliation: Department of Physiopathology, Universidade Metropolitana de Santos, Santos, SP, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sementilli
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, Scotland, UK.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Ross
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, Scotland, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morgan
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK. p.j.mccaffery@abdn.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCaffery
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D019898:Autocrine Communication; D001921:Brain / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000201:enzymology; D003342:Corpus Striatum / Q000201:enzymology; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D019899:Paracrine Communication; D051381:Rats; D050697:Retinal Dehydrogenase / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; C000607078:CYP26A1 protein, human; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase
keywords: CYP26A1; CYP26B1; Dentate gyrus; Gradient; Hippocampus; Infrapyramidal; Retinoic acid catabolism; Suprapyramidal