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Event: 2201

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Agonism, Retinoic acid receptor

Short name

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RAR agonism

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status
RAR agonism during neurodevelopment leading to impaired learning and memory	MolecularInitiatingEvent	Diana Lupu (send email)	Under development: Not open for comment. Do not cite
RAR agonism during neurodevelopment leading to microcephaly	MolecularInitiatingEvent	Diana Lupu (send email)	Under development: Not open for comment. Do not cite
RAR agonism during neurodevelopment leading to impaired locomotor function	MolecularInitiatingEvent	Diana Lupu (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
During brain development	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Biological state: Retinoic acid receptors (RARs) are nuclear receptors encoded by three distinct genes Rara, Rarb and Rarg (encoding RARα, RARβ, and RARγ, respectively). RARs are evolutionarily conserved in vertebrate taxa and mediate physiological processes during development and across the lifespan (reviewed in Mark et al., 2009; Duong and Rochette-Egly 2011). Functionally, RARs are ligand-activated transcription factors that require formation of heterodimers with retinoid X receptors (RXRs) α, β, and γ, and are activated by several retinoids, including all-trans-retinoic acid and its isomer, 9-cis-retinoic acid. Structurally, RARs include (1) a ligand-binding domain (LBD), (2) a DNA-binding domain (DBD) which can bind specific DNA sequences known as retinoic acid response elements (RAREs) and (3) a transcriptional activation domain (reviewed in Chambon 1996, Rastinejad 2022). In the absence of ligand, the DNA-bound RAR/RXR heterodimers are associated with corepressors, such as nuclear receptor corepressor 1 and 2 (NCoR1 and NCoR2), and constitutively repress transcription (Kurokawa et al., 1995; le Maire et al., 2010).

Biological compartments: The expression pattern of Rar genes during development has been studied in various species, with Rara having a widespread expression, while Rarb and Rarg show more complex, region-specific expression in both neural and non-neural tissues (reviewed in Dollé 2009). Rarg, although present in the embryo during neurulation, has not been detected at later prenatal and early postnatal stages of brain development in rodents (Ruberte et al., 1993; Zetterström et al., 1999). Rara and Rarb are expressed early in the neural tube epithelium and are involved in the patterning of hindbrain rhombomere segmentation (Ruberte et al., 1991; Dup é et al., 1999a). Later on during brain development, Rara and Rarb are co-expressed in the medulla oblongata, with Rarb showing localization in the somatic and visceral motor nuclei (Ruberte et al., 1993). Rara and Rarb are also co-expressed in the developing forebrain, particularly in the corpus striatum, hippocampus and cortex (Ruberte et al., 1993; Yamagata et al., 1994). Rarb is additionally present in the olfactory tubercle, and in the choroid plexuses and meninges (Ruberte et al., 1993).

General role in biology: Retinoic acid receptors function as ligand-dependent transcriptional regulators of target genes involved in cellular differentiation, proliferation and apoptosis (Gudas and Wagner 2011; Noy 2010), and therefore play crucial roles in a multitude of biological processes, such as embryonic and fetal development, including cardiovascular, respiratory and CNS development, reproduction and immunity (reviewed in Mark et al., 2009; McCaffery and Dräger 2000; Clagett-Dame and Knutson 2011; Damdimoupoulou 2019; Erkelens and Mebius 2017).

RA signalling has been extensively studied for its role in early neurodevelopmental events such as patterning of hindbrain segmentation, and there is evidence from pharmacologic and genetic ablation studies also pointing toward a later role in forebrain development (Rhinn and Doll é 2012; Schneider et al., 2001; Ribes et al., 2006; Halilagic et al., 2007; Chatzi et al., 2011; Molotkova et al., 2007; LaMantia et al., 1993).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

There are yet no OECD methods available to measure RAR receptor agonism, although retinoic signalling has been acknowledged as one of the major endocrine pathways that can be subject to chemical perturbations (OECD 2012) and the need for its inclusion in future chemical testing strategies has been recently highlighted (Grignard et al., 2020).

RAR receptor transactivation can be measured indirectly by using cell-based reporter gene assays. Expression of luciferase and β-galactosidase reporters driven by RARE-containing promoters have been employed (Idres et al., 2002; Moise et al., 2009; Zolfaghari et al., 2019; Ababon et al., 2016) and RAR reporter assays are commercially available (e.g. INDIGO Biosciences).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

References

List of the literature that was cited for this KE description. More help

1. Mark M, Ghyselinck NB, Chambon P. Function of retinoic acid receptors during embryonic development. Nucl Recept Signal. 2009;7:e002.

2. Duong V, Rochette-Egly C. The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim Biophys Acta. 2011;1812(8):1023-31.

3. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996;10(9):940-54.

4. Rastinejad F. Retinoic acid receptor structures: the journey from single domains to full-length complex. J Mol Endocrinol. 2022;69(4):T25-T36.

5. Kurokawa R, Söderström M, Hörlein A, Halachmi S, Brown M, Rosenfeld MG, et al. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature. 1995;377(6548):451-4.

6. le Maire A, Teyssier C, Erb C, Grimaldi M, Alvarez S, de Lera AR, et al. A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat Struct Mol Biol. 2010;17(7):801-7.

7. Dollé P. Developmental expression of retinoic acid receptors (RARs). Nucl Recept Signal. 2009;7:e006.

8. Ruberte E, Friederich V, Chambon P, Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. III. Their differential transcript distribution during mouse nervous system development. Development. 1993;118(1):267-82.

9. Zetterström RH, Lindqvist E, Mata de Urquiza A, Tomac A, Eriksson U, Perlmann T, et al. Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci. 1999;11(2):407-16.

10. Ruberte E, Dolle P, Chambon P, Morriss-Kay G. Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development. 1991;111(1):45-60.

11. Dupé V, Ghyselinck NB, Wendling O, Chambon P, Mark M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development. 1999;126(22):5051-9.

12. Yamagata T, Momoi MY, Yanagisawa M, Kumagai H, Yamakado M, Momoi T. Changes of the expression and distribution of retinoic acid receptors during neurogenesis in mouse embryos. Brain Res Dev Brain Res. 1994;77(2):163-76.

13. Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226(2):322-30.

14. Noy N. Between death and survival: retinoic acid in regulation of apoptosis. Annu Rev Nutr. 2010;30:201-17.

15. McCaffery P, Dräger UC. Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor. Cytokine Growth Factor Rev. 2000;11(3):233-49.

16. Clagett-Dame M, Knutson D. Vitamin A in reproduction and development. Nutrients. 2011;3(4):385-428.

17. Damdimopoulou P, Chiang C, Flaws JA. Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis. Reprod Toxicol. 2019;87:32-41.

18. Erkelens MN, Mebius RE. Retinoic Acid and Immune Homeostasis: A Balancing Act. Trends Immunol. 2017;38(3):168-80.

19. Rhinn M, Dollé P. Retinoic acid signalling during development. Development. 2012;139(5):843-58.

20. Schneider RA, Hu D, Rubenstein JL, Maden M, Helms JA. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development. 2001;128(14):2755-67.

21. Ribes V, Wang Z, Dollé P, Niederreither K. Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development. 2006;133(2):351-61.

22. Halilagic A, Ribes V, Ghyselinck NB, Zile MH, Dollé P, Studer M. Retinoids control anterior and dorsal properties in the developing forebrain. Dev Biol. 2007;303(1):362-75.

23. Chatzi C, Brade T, Duester G. Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. PLoS Biol. 2011;9(4):e1000609.

24. Molotkova N, Molotkov A, Duester G. Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone. Dev Biol. 2007;303(2):601-10.

25. LaMantia AS, Colbert MC, Linney E. Retinoic acid induction and regional differentiation prefigure olfactory pathway formation in the mammalian forebrain. Neuron. 1993;10(6):1035-48.

26. OECD. Detailed Review Paper on the State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors2012.

27. Grignard E, Håkansson H, Munn S. Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: The European viewpoint. Reprod Toxicol. 2020;93:250-8.

28. Idres N, Marill J, Flexor MA, Chabot GG. Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers. J Biol Chem. 2002;277(35):31491-8.

29. Moise AR, Alvarez S, Domínguez M, Alvarez R, Golczak M, Lobo GP, et al. Activation of retinoic acid receptors by dihydroretinoids. Mol Pharmacol. 2009;76(6):1228-37.

30. Zolfaghari R, Mattie FJ, Wei CH, Chisholm DR, Whiting A, Ross AC. CYP26A1 gene promoter is a useful tool for reporting RAR-mediated retinoid activity. Anal Biochem. 2019;577:98-109.

31. Ababon MR, Li BI, Matteson PG, Millonig JH. Quantitative Measurement of Relative Retinoic Acid Levels in E8.5 Embryos and Neurosphere Cultures Using the F9 RARE-Lacz Cell-based Reporter Assay. J Vis Exp. 2016(115).