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.

Optic nerve injury upregulates retinoic acid signaling in the adult frog visual system

“…In normal adult frog retinas, we found that all the components of RA signaling are present to some extent in or near the RGCs, namely, the synthetic enzyme RALDH2, the binding proteins CRABPI and II, all three receptor subtypes, and finally the catabolic enzyme CYP26A1 which prevents more widespread diffusion of the lipophilic molecule (Stoney et al, 2015). …”

“…In developing mouse brain, some RA activity (and, presumably, synthesis) is detected in the tectum, but later in development it is superseded by RA originating in the RGC axons, which also contain RALDH1 and 3 (Luo et al, 2004). There is no reported expression of CYP26 in adult tectal structures (Stoney et al, 2015), and there is only one other study to localize RARs immunochemically to the tectum, and that is in the chick (Propping et al, 2007). …”

“…During development, gradients of the lipophilic RA are set up by differential localization of its synthetic and catabolic enzymes, RALDH and CYP26 respectively, leading to the conclusion that RA has a paracrine role (Stoney et al, 2015). However, in some regions of adult rat and human brain, such as the hippocampus, RALDH and CYP26 co-localize in the same neurons, suggesting an autocrine intracellular signaling system (Stoney et al, 2015).…”

“…However, in some regions of adult rat and human brain, such as the hippocampus, RALDH and CYP26 co-localize in the same neurons, suggesting an autocrine intracellular signaling system (Stoney et al, 2015). …”

“…After development is over, RA signaling has a role in the CNS of adult animals, particularly in areas of high neuronal plasticity such as the hippocampus, cortex, and striatum (Goodman et al, 2012; Maden, 2007; McCaffery et al, 2006; Shearer et al, 2012; Stoney et al, 2015; Thompson Haskell et al, 2002). It has also recently been implicated in the control of rhythms within the brain (Ransom et al, 2014).…”