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

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

doi:10.1007/s00429-015-1102-z

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.

Highlights

Retinoic acid (RA), synthesized from vitamin A through a series of oxidative steps, is a lipid regulator of transcription and is the mediator of the majority of vitamin A’s functions
Cyp26a1 gene expression is reported to be weak in the adult mouse brain (Abu-Abed et al 2002) and polymerase chain reaction (PCR) analysis of the adult rat brain (Fig. 1a) shows similar weak expression, with almost no Cyp26a1 transcript detected in the hippocampus, hypothalamus, cerebellum and olfactory bulb
In situ hybridization showed that, Cyp26b1 is widely distributed in the rat forebrain, it has a patterned rather than homogeneous distribution and is strongly expressed in subregions of the cortex, amygdala, striatum and hippocampus (Fig. 1c–e)

Summary

Introduction

Retinoic acid (RA), synthesized from vitamin A through a series of oxidative steps, is a lipid regulator of transcription and is the mediator of the majority of vitamin A’s functions. In addition to the enzymes that synthesize RA, the binding proteins transporting RA in the cytoplasm and the nuclear retinoic acid receptors (RARs) that transduce the signal, the capacity to switch off the RA signal is vital for the action of the RA signaling pathway. This task is performed by a subset of the cytochrome P450 family: Cyp26a1, Cyp26b1 and Cyp26c1 (McCaffery and Simons 2007; Ross and Zolfaghari 2011). In contrast to its counterparts, Cyp26c1 is expressed to a lesser extent in the embryo and its loss in the mouse has few effects, mutation in the human results in a range of facial skin defects (Slavotinek et al 2013)

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