Retinoic Acid Fluctuation Activates an Uneven, Direction-Dependent Network-Wide Robustness Response in Early Embryogenesis

Parihar, Madhur; Bendelac-Kapon, Liat; Gur, Michal; Abbou, Tali; Belorkar, Abha; Achanta, Sirisha; Kinberg, Keren; Vadigepalli, Rajanikanth; Fainsod, Abraham

doi:10.3389/fcell.2021.747969

Cited by 9 publications

(4 citation statements)

References 95 publications

(151 reference statements)

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“…To our surprise, many of the genes that were unaffected by dnRXRα overexpression (ratio of expression levels in rexinoid-treated dnRXRα-rafts to rexinoid-treated EV-rafts above 0.8) turned out to be bona fide ATRA targets. In fact, this is in agreement with the known differential sensitivity of ATRA target genes to ATRA concentration [ 53 , 54 ] and suggests that the residual levels of native RXRα-RAR heterodimers together with in situ available ATRA are sufficient for transcriptional activation of these genes, and treatment with RXRα agonists, which raise ATRA levels, does not enhance their transcription.…”

Section: Discussionsupporting

confidence: 84%

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

Belyaeva,

Klyuyeva,

Vyas

et al. 2024

PLoS ONE

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Rexinoids are agonists of nuclear rexinoid X receptors (RXR) that heterodimerize with other nuclear receptors to regulate gene transcription. A number of selective RXR agonists have been developed for clinical use but their application has been hampered by the unwanted side effects associated with the use of rexinoids and a limited understanding of their mechanisms of action across different cell types. Our previous studies showed that treatment of organotypic human epidermis with the low toxicity UAB30 and UAB110 rexinoids resulted in increased steady-state levels of all-trans-retinoic acid (ATRA), the obligatory ligand of the RXR-RAR heterodimers. Here, we investigated the molecular mechanism underlying the increase in ATRA levels using a dominant negative RXRα that lacks the activation function 2 (AF-2) domain. The results demonstrated that overexpression of dnRXRα in human organotypic epidermis markedly reduced signaling by resident ATRA, suggesting the existence of endogenous RXR ligand, diminished the biological effects of UAB30 and UAB110 on epidermis morphology and gene expression, and nearly abolished the rexinoid-induced increase in ATRA levels. Global transcriptome analysis of dnRXRα-rafts in comparison to empty vector-transduced rafts showed that over 95% of the differentially expressed genes in rexinoid-treated rafts constitute direct or indirect ATRA-regulated genes. Thus, the biological effects of UAB30 and UAB110 are mediated through the AF-2 domain of RXRα with minimal side effects in human epidermis. As ATRA levels are known to be reduced in certain epithelial pathologies, treatment with UAB30 and UAB110 may represent a promising therapy for normalizing the endogenous ATRA concentration and signaling in epithelial tissues.

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Section: Discussionsupporting

confidence: 84%

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

Belyaeva,

Klyuyeva,

Vyas

et al. 2024

PLoS ONE

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“…Usurping retinol and retinaldehyde dehydrogenase for alcohol detoxification also comes at the cost of reduced synthesis of RA, particularly when it is essential to guide cellular spatiotemporal patterning [33]. Most individuals who are prenatally exposed to alcohol do not develop FASD [17], which is likely due to the robustness of the RA signaling network being able to adjust to acute PAE accordingly [43]. However, when damaging variants are within the RA and alcohol metabolism genes and already perturb the RA pathway, PAE as an additional factor might disrupt the pathway so severely that FASD develops.…”

Section: Discussionmentioning

confidence: 99%

Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes

McKay,

Petrelli,

Pind

et al. 2024

Biomolecules

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Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE.

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“…Also in the rescue experiments, early gastrula showed the highest sensitivity for NTC defect induction by reduced RA signaling. The beginning of gastrulation marks the onset of RA signaling ( Ang and Duester, 1999 ; Niederreither et al, 1999 ; Grandel et al, 2002 ; Gur et al, 2022b ) and RA signaling onset follows the transcriptional activation of the retinaldehyde dehydrogenases, mainly aldh1a2 but also aldh1a3, at the initiation of gastrulation in the embryonic organizer ( Chen et al, 2001 ; Shabtai et al, 2018 ; Parihar et al, 2021 ; Gur et al, 2022a ; Lupo et al, 2005 ). In agreement, early RA signaling localizes to the embryonic organizer as shown in multiple vertebrate models ( Rossant et al, 1991 ; Hogan et al, 1992 ; Deltour et al, 1996 ; Yelin et al, 2005 ; Samarut et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion

Edri,

Cohen,

Shabtai

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Neural tube defects (NTDs) are among the most debilitating and common developmental defects in humans. The induction of NTDs has been attributed to abnormal folic acid (vitamin B9) metabolism, Wnt and BMP signaling, excess retinoic acid (RA), dietary components, environmental factors, and many others. In the present study we show that reduced RA signaling, including alcohol exposure, induces NTDs.Methods:Xenopus embryos were exposed to pharmacological RA biosynthesis inhibitors to study the induction of NTDs. Embryos were treated with DEAB, citral, or ethanol, all of which inhibit the biosynthesis of RA, or injected to overexpress Cyp26a1 to reduce RA. NTD induction was studied using neural plate and notochord markers together with morphological analysis. Expression of the neuroectodermal regulatory network and cell proliferation were analyzed to understand the morphological malformations of the neural plate.Results: Reducing RA signaling levels using retinaldehyde dehydrogenase inhibitors (ethanol, DEAB, and citral) or Cyp26a1-driven degradation efficiently induce NTDs. These NTDs can be rescued by providing precursors of RA. We mapped this RA requirement to early gastrula stages during the induction of neural plate precursors. This reduced RA signaling results in abnormal expression of neural network genes, including the neural plate stem cell maintenance genes, geminin, and foxd4l1.1. This abnormal expression of neural network genes results in increased proliferation of neural precursors giving rise to an expanded neural plate.Conclusion: We show that RA signaling is required for neural tube closure during embryogenesis. RA signaling plays a very early role in the regulation of proliferation and differentiation of the neural plate soon after the induction of neural progenitors during gastrulation. RA signaling disruption leads to the induction of NTDs through the mis regulation of the early neuroectodermal network, leading to increased proliferation resulting in the expansion of the neural plate. Ethanol exposure induces NTDs through this mechanism involving reduced RA levels.

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Retinoic Acid Fluctuation Activates an Uneven, Direction-Dependent Network-Wide Robustness Response in Early Embryogenesis

Cited by 9 publications

References 95 publications

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

The retinoid X receptor has a critical role in synthetic rexinoid-induced increase in cellular all-trans-retinoic acid

Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes

Alcohol induces neural tube defects by reducing retinoic acid signaling and promoting neural plate expansion

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