Signalling 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 in mouse models by clearing amyloid plaque and by promoting neurogenesis. In this paper, we show that RXR-initiated bexarotene signalling generates additional neurons both during normal X. laevis development and in ectodermal explants in which bone morphogenetic protein (BMP) signalling is inhibited. Differential gene expression analysis between ectodermal explants taken from uninjected embryos and from embryos co-injected with mRNA that expresses Noggin, a BMP antagonist, and RXRβ identifies genes mediating the transition from an epidermal to a neural fate. The explants express genes associated with an anterior neural fate, but not a 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 signalling 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.