Retinoic acid receptors and retinoid X receptors in the mature retina: Subtype determination and cellular distribution

Janssen, J.J.M.; Kuhlmann, E.D.; Vugt, A.H.M. van; Winkens, H.J.; Janssen, Albert P. M.; Deutman, August F.; Driessen, C.A.G.G.

doi:10.1076/ceyr.19.4.338.5307

Cited by 30 publications

(24 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to DNA binding and interaction with receptor cofactors, recent studies suggest that subcellular distribution of RXR and its dimerization partners represents another mechanism that regulates their biological activity. Despite being localized in the nucleus in many cell types, RXR (12,27) and its partners, including RARs (12). TRs (2,6,92), VDR (57,58), and Nur77 (30,40), were found in the cytoplasm in certain cell types and stages during development or under different cellular environments.…”

mentioning

confidence: 99%

Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting

Cao

Lin

et al. 2004

Molecular and Cellular Biology

164

108

View full text Add to dashboard Cite

Retinoid X receptor (RXR) plays a central role in the regulation of intracellular receptor signaling pathways by acting as a ubiquitous heterodimerization partner of many nuclear receptors, including the orphan receptor Nur77 (also known as thyroid hormone receptor 3 or NGFI-B), which translocates from the nucleus to mitochondria, where it interacts with Bcl-2 to induce apoptosis. Here, we report that RXR␣ is required for nuclear export and mitochondrial targeting of Nur77 through their unique heterodimerization that is mediated by dimerization interfaces located in their DNA-binding domain. The effects of RXR␣ are attributed to a putative nuclear export sequence (NES) present in its carboxyl-terminal region. RXR␣ ligands suppress NES activity by inducing RXR␣ homodimerization or altering RXR␣/Nur77 heterodimerization. The RXR␣ NES is also silenced by RXR␣ heterodimerization with retinoic acid receptor or vitamin D receptor. Consistently, we were able to show that the mitochondrial targeting of the RXR␣/Nur77 heterodimer and its induction of apoptosis are potently inhibited by RXR ligands. Together, our results reveal a novel nongenotropic function of RXR␣ and its involvement in the regulation of the Nur77-dependent apoptotic pathway.Retinoid X receptors (RXRs) belong to the nuclear receptor superfamily, consisting of a large number of ligand-regulated transcription factors that mediate the diverse physiological functions of their ligands, such as steroid hormones, retinoids, thyroid hormone, and vitamin D 3 , in embryonic development, growth, differentiation, apoptosis, and homeostasis (29, 46). The superfamily also includes many orphan receptors whose ligands remain to be identified. All nuclear receptors consist of three major domains: the variable length N-terminal domain, the well-conserved DNA-binding domain (DBD), and the ligand-binding domain (LBD) (29,46). The C-terminal LBD is multifunctional and, in addition to harboring a ligand-binding site, contains regions for receptor dimerization and the ligand-dependent transactivation function (AF-2). The DBD also contains a dimerization interface that determines target gene specificity (38,55,60,85). RXRs mediate retinoid signaling through the RXR/retinoic acid receptor (RAR) heterodimer and the RXR/RXR homodimer (29,46,89). In addition, RXRs form heterodimers with many members of the subfamily 1 nuclear receptors, including vitamin D receptor (VDR), peroxisome proliferator-activated receptor (PPAR), and thyroid hormone receptor (TR), as well as several orphan receptors, such as liver X receptor, pregnane X receptor, constitutively activated receptor, and Nur77 (TR3 or NGFI-B) (29, 46). RXRs, therefore, play an essential role in the regulation of multiple nuclear hormone-signaling pathways through their unique and potent dimerization capacity. The vitamin A metabolite, 9-cis-retinoic acid (9-cis-RA), is a high-affinity ligand for RXRs (22,39). It induces transactivation of the RXR homodimer (26,29,46,88,90) and certain RXR heterodimers, such as the RXR/Nur77 ...

show abstract

mentioning

confidence: 99%

Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting

Cao

Lin

et al. 2004

Molecular and Cellular Biology

164

108

View full text Add to dashboard Cite

show abstract

“…This opens the possibility that transactivators of S-and M-opsin with regulatory function during early development also play a role for the maintenance of opsin identity in mature cones. Interestingly, TR␤2, RXR␥, ROR␣, and ROR␤ remain expressed in the adult retina (Janssen et al, 1999;Mori et al, 2001;Srinivas et al, 2006;Applebury et al, 2007;Fujieda et al, 2009) but their role in differentiated cones is unexplored. Future research should devise methods including conditional, cell-specific gene manipulation to reveal the role of the various transcription factors in cone development and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone Controls Cone Opsin Expression in the Retina of Adult Rodents

Glaschke¹,

Weiland²,

Turco³

et al. 2011

J. Neurosci.

103

View full text Add to dashboard Cite

Mammalian retinas display an astonishing diversity in the spatial arrangement of their spectral cone photoreceptors, probably in adaptation to different visual environments. Opsin expression patterns like the dorsoventral gradients of short-wave-sensitive (S) and middle-to long-wave-sensitive (M) cone opsin found in many species are established early in development and thought to be stable thereafter throughout life. In mouse early development, thyroid hormone (TH), through its receptor TR␤2, is an important regulator of cone spectral identity. However, the role of TH in the maintenance of the mature cone photoreceptor pattern is unclear. We here show that TH also controls adult cone opsin expression. Methimazole-induced suppression of serum TH in adult mice and rats yielded no changes in cone numbers but reversibly altered cone patterns by activating the expression of S-cone opsin and repressing the expression of M-cone opsin. Furthermore, treatment of athyroid Pax8 Ϫ/Ϫ mice with TH restored a wild-type pattern of cone opsin expression that reverted back to the mutant S-opsin-dominated pattern after termination of treatment. No evidence for cone death or the generation of new cones from retinal progenitors was found in retinas that shifted opsin expression patterns. Together, this suggests that opsin expression in terminally differentiated mammalian cones remains subject to control by TH, a finding that is in contradiction to previous work and challenges the current view that opsin identity in mature mammalian cones is fixed by permanent gene silencing.

show abstract

“…Several lines of evidence have shown that RA is a potential endogenous neuroactive substance in the vertebrate retina including the presence of precursors, synthetic enzymes, binding proteins, nuclear receptors, and demonstrated RA release (3,4,6,(33)(34)(35)(36)(37)(38)(39). Because RA is membrane permeant, it is highly diffusible in tissue.…”

Section: Discussionmentioning

confidence: 99%