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Signaling through RXRβ and its agonist, bexarotene, promotes neuron formation in Xenopus laevis embryos

ABSTRACT: Retinoic acid, acting through RAR/RXR nuclear receptors, is required for neuronal differentiation in Xenopus laevis. Bexarotene, characterised as a pan-RXR agonist, reduces the symptoms of Alzheimer’s disease (AD) in mouse models by clearing amyloid plaque and by promoting neurogenesis. In this paper, we show that RXR-initiated bexarotene signaling generates additional neurons both during normal Xenopus laevis development and in ectodermal explants in which BMP- signaling is inhibited. Differential gene expression between ectodermal explants taken from uninjected and embryos co-injected with mRNA that expresses Noggin, a BMP antagonist, and RXRβ identifies genes mediating change from an epidermal to a neural fate. The explants express genes associated with an anterior neural, but not neuronal fate. The addition of bexarotene to equivalent co-injected explants activates genes that promote neuronal differentiation and posterior character, including genes of the canonical Wnt signaling pathway. Xenopus ectodermal explants therefore provide a simple and efficient tool to identify novel retinoid agonists that promote neuronal differentiation. The genes expressed in response to bexarotene are consistent with a pathway to neuronal differentiation allied to standard retinoid signalling.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE330857 | GEO | 2026/06/18

REPOSITORIES: GEO

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Project description:Transcriptional targets of neurogenin (Ngnr1) were identified by over-expression of an inducible form of neurogenin in Xenopus ectodermal explants. The effects of co-expressing the nucleoprotein geminin on Ngnr1-dependent target gene transactivation were defined. Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized both neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural bHLH transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. Geminin is highly expressed in undifferentiated neuronal precursor cells but is downregulated prior to differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis. A dexamethasone-inducible (GR ligand binding domain fused) form of Xenopus neurogenin-related 1, NgnrGR, was over-expressed in Xenopus embryonic ectodermal explants, in the presence or absence of over-expressed geminin. Induction of Ngnr1 activity was used to define direct targets as previously described (EMBO J. 26(24): 5093-5108). The ability of geminin to suppress Ngnr1-dependent transactivation of its target gene programs was determined.

Project description:Background: The retinoid X receptor (RXR) is a ligand-activated nuclear receptor that heterodimerizes with numerous partners to regulate diverse transcriptional programs. RXR agonists, in-cluding the FDA-approved drug bexarotene, show anti-tumor activity but are limited by adverse side effects. V-125 is a next-generation RXR agonist engineered for improved se-lectivity, pharmacokinetics, and reduced lipogenic effects. This study compares the mo-lecular and functional effects of V-125 and bexarotene in HER2⁺ breast cancer models. Methods: Female MMTV-Neu mice bearing mammary tumors were treated with control, V-125 (100 mg/kg diet), or bexarotene (100 mg/kg diet) for 10 days. RNA sequencing was used to identify differentially expressed genes and pathways. Candidate targets were validated by qPCR and immunohistochemistry (IHC). Immune modulation was evaluated by IHC staining for CD8 cells and CD206⁺ macrophages in tumors to capture the tumor microen-vironment. Functional assays in JIMT-1 human HER2⁺ cells assessed RXR target activation and clonogenic potential in tumor cells. Results: V-125 induced broader transcriptional changes than bexarotene, including selective up-regulation of Nrg1, Nfasc, Lrrc26, and Chi3l1 genes associated with improved patient sur-vival. Pathway analysis revealed regulation of immune activation, cancer signaling, and lipid metabolism. Both V-125 and bexarotene suppressed colony formation in JIMT-1 cells, confirming previous observations about RXR-dependent inhibition of tumor cell growth. Moreover, V-125 in vivo had distinct capabilities to increase CD8 cell infiltration and reduced CD206⁺ macrophages, whereas bexarotene did not. Conclusion: V-125 but not bexarotene reprograms tumor transcriptional programs and the immune landscape in an anti-tumor manner in MMTV-neu mouse model and in in vitro models of HER2⁺ breast cancer. This highlights its promise as a selective RXR agonist with anti-tu-mor and immunomodulatory activity in HER2⁺ breast cancer.

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Signaling through RXRβ and its agonist, bexarotene, promotes neuron formation in Xenopus laevis embryos

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