Astrocytes as a regulated source of retinoic acid for the brain

Shearer, Kirsty; Fragoso, Yára Dadalti; Clagett‐Dame, Margaret; McCaffery, Peter

doi:10.1002/glia.22412

Cited by 28 publications

(20 citation statements)

References 42 publications

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“…To screen for impaired RA synthesis in tumors, we first compared the transcript levels of retinol‐synthesizing enzymes (RDH10, RDH16, dehydrogenase/reductase member 9 [DHRS9], ALDH1A1, ALDH1A2, and ALDH1A3) in glioblastoma tissues ( n = 26) and normal brain biopsies ( n = 8) (Napoli, ; Shearer et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…To screen for impaired RA synthesis in tumors, we first compared the transcript levels of retinol-synthesizing enzymes (RDH10, RDH16, dehydrogenase/reductase member 9 [DHRS9], ALDH1A1, ALDH1A2, and ALDH1A3) in glioblastoma tissues (n 5 26) and normal brain biopsies (n 5 8) (Napoli, 2012;Shearer et al, 2012). Consistent with our hypothesis of impaired RA synthesis in glioblastoma, the expression of ALDH1A1, ALDH1A2, ALDH1A3, and DHRS9 was distinctly downregulated in tumors as compared with nontumorous brain tissue ( Fig.…”

Section: Downregulation Of Transcripts Associated With Ra Synthesis Imentioning

confidence: 99%

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Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma

Campos

Weisang

Osswald

et al. 2015

Glia

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Measuring concentrations of the differentiation-promoting hormone retinoic acid (RA) in glioblastoma tissues would help to understand the reason why RA treatment has been inefficient in clinical trials involving brain tumor patients. Here, we apply a recently established extraction and measurement protocol to screen glioblastoma tissues for the levels of the RA precursor retinol and biologically active RA. Combining this approach with mRNA analyses of 26 tumors and 8 normal brains, we identify a multifaceted disturbance of RA synthesis in glioblastoma, involving multiple aldehyde dehydrogenase 1 family and retinol dehydrogenase enzymes. Through database studies and methylation analyses, we narrow down chromosomal deletions and aberrant promoter hypermethylation as potential mechanisms accounting for these alterations. Employing chromatin immunoprecipitation analyses and cell-culture studies, we further show that chromatin at RA target genes is poised to RA substitution, but most glioblastoma cell cultures are completely resistant to RA treatment. This paradoxical RA response is unrelated to alternative RA signaling through the fatty acid-binding protein 5/peroxisome proliferator-activated receptor delta axis. Our data suggest a multifaceted disturbance of RA synthesis in glioblastoma and contribute to reconsider current RA treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Downregulation Of Transcripts Associated With Ra Synthesis Imentioning

confidence: 99%

Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma

Campos

Weisang

Osswald

et al. 2015

Glia

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“…Moreover, we previously showed that RA treatment increases hippocampal expression of RARβ in middle‐aged rats, whereas RARα is decreased . Interestingly, it has been shown that, under conditions of low vitamin A, a local increase of RA could be detected in astrocytes to maintain a source of RA in the brain, suggesting that some RA receptors could be up‐regulated in VAD conditions …”

Section: Discussionmentioning

confidence: 96%

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway

Bonhomme

Alfos

Webster

et al. 2019

J Neuroendocrinology

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Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid‐associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11β‐HSD1 expression following a novelty‐induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11β‐HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD‐induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11β‐HSD1 expression. Vitamin A supplementation normalises VAD‐induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11β‐HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11β‐HSD1.

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“…Such a scenario, where functional cells require exogenous RA produced by accessory cells for their survival and development appears to be a common theme among a variety of physiological systems. For example, gonadal germ cell fate is dictated by RA produced by mesonephroi (Bowles et al, 2006) whereas astrocytes provide a regulated source of RA for the brain (Shearer et al, 2012). RA is also provided to peripheral T lymphocytes by dendritic cells and this has been shown to imprint gut-homing specificity by enhancing the expression of integrin alpha4beta7 and chemokine receptor CCR9, an effect suppressed by the ALDH1A inhibitor citral (Iwata et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T‐lineage tumours

et al. 2014

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SummaryThe class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines. This revealed that T-ALL proliferation had a higher sensitivity to modulation of ALDH1A activity and RA signalling as compared to ALL cell lines of B-lineage. Consistent with these findings, the genes most highly correlated with ALDH1A2 expression were involved in cell proliferation and apoptosis. Evidence that such genes may be targets of regulation via RA signalling initiated by ALDH1A activity was provided by the TNFRSF10B gene, encoding the apoptotic death receptor TNFRSF10B (also termed TRAIL-R2), which negatively correlated with ALDH1A2 and showed elevated transcription following treatment of T-ALL cell lines with the ALDH1A inhibitor citral (3,7-dimethyl-2,6-octadienal). These data indicate that ALDH1A expression is a common event in T-ALL and supports a role for these enzymes in the pathobiology of this disease.

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Astrocytes as a regulated source of retinoic acid for the brain

Cited by 28 publications

References 42 publications

Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma

Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway

Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T‐lineage tumours

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