Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis

Patrick N. Stoney, Yara Fragoso, Reem Bu Saeed, Anna Ashton, Timothy Goodman, Claire Simons, Mohamed S. Gomaa, Angelo Sementilli, Leonardo Sementilli, Alexander W. Ross, Peter J. Morgan, Peter J. McCaffery

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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 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.
Original languageEnglish
Pages (from-to)3315-3326
Number of pages12
JournalBrain Structure and Function
Volume221
Issue number6
Early online date15 Sep 2015
DOIs
Publication statusPublished - Jul 2016

Fingerprint

Tretinoin
Homeostasis
Brain
Enzymes
Neurons
Retinoic Acid 4-Hydroxylase
Autocrine Communication
Neurogenesis
Retinoids
Enzyme Inhibitors
Regulator Genes
Cytoplasmic and Nuclear Receptors
Neuroblastoma
Morphogenesis
Cerebral Cortex
Transcriptional Activation
Embryonic Structures
Maintenance
Cell Proliferation

Keywords

  • Retinoic acid catabolism
  • CYP26A1
  • CYP26B1
  • Gradient
  • Hippocampus
  • Suprapyramidal
  • Infrapyramidal
  • Dentate gyrus

Cite this

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis. / Stoney, Patrick N.; Fragoso, Yara; Bu Saeed, Reem; Ashton, Anna; Goodman, Timothy; Simons, Claire ; Gomaa, Mohamed S.; Sementilli, Angelo; Sementilli, Leonardo ; Ross, Alexander W.; Morgan, Peter J.; McCaffery, Peter J.

In: Brain Structure and Function, Vol. 221, No. 6, 07.2016, p. 3315-3326.

Research output: Contribution to journalArticle

Stoney, PN, Fragoso, Y, Bu Saeed, R, Ashton, A, Goodman, T, Simons, C, Gomaa, MS, Sementilli, A, Sementilli, L, Ross, AW, Morgan, PJ & McCaffery, PJ 2016, 'Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis', Brain Structure and Function, vol. 221, no. 6, pp. 3315-3326. https://doi.org/10.1007/s00429-015-1102-z
Stoney, Patrick N. ; Fragoso, Yara ; Bu Saeed, Reem ; Ashton, Anna ; Goodman, Timothy ; Simons, Claire ; Gomaa, Mohamed S. ; Sementilli, Angelo ; Sementilli, Leonardo ; Ross, Alexander W. ; Morgan, Peter J. ; McCaffery, Peter J. / Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis. In: Brain Structure and Function. 2016 ; Vol. 221, No. 6. pp. 3315-3326.
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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 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.",
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