Abstract
BackgroundThe mammalian thalamus relays sensory information from the periphery to the cerebral cortex for cognitive processing via the thalamocortical tract. The thalamocortical tract forms during embryonic development controlled by mechanisms that are not fully understood. β-catenin is a nuclear and cytosolic protein that transduces signals from secreted signaling molecules to regulate both cell motility via the cytoskeleton and gene expression in the nucleus. In this study we tested whether β-catenin is likely to play a role in thalamocortical connectivity by examining its expression and activity in developing thalamic neurons and their axons.ResultsAt embryonic day (E)15.5, the time when thalamocortical axonal projections are forming, we found that the thalamus is a site of particularly high β-catenin mRNA and protein expression. As well as being expressed at high levels in thalamic cell bodies, β-catenin protein is enriched in the axons and growth cones of thalamic axons and its growth cone concentration is sensitive to Netrin-1. Using mice carrying the β-catenin reporter BAT-gal we find high levels of reporter activity in the thalamus. Further, Netrin-1 induces BAT-gal reporter expression and upregulates levels of endogenous transcripts encoding β-actin and L1 proteins in cultured thalamic cells. We found that β-catenin mRNA is enriched in thalamic axons and its 3'UTR is phylogenetically conserved and is able to direct heterologous mRNAs along the thalamic axon, where they can be translated.ConclusionWe provide evidence that β-catenin protein is likely to be an important player in thalamocortcial development. It is abundant both in the nucleus and in the growth cones of post-mitotic thalamic cells during the development of thalamocortical connectivity and β-catenin mRNA is targeted to thalamic axons and growth cones where it could potentially be translated. β-catenin is involved in transducing the Netrin-1 signal to thalamic cells suggesting a mechanism by which Netrin-1 guides thalamocortical development.
Highlights
The mammalian thalamus relays sensory information from the periphery to the cerebral cortex for cognitive processing via the thalamocortical tract
Using a combination of in situ hybridisation, green fluorescent protein (GFP) reporter transgenes, and quantitative RT-PCR we showed that b-catenin messenger RNA (mRNA) is enriched in thalamic axons and sequence elements in its highly conserved 3’untranslated region (UTR) enhance protein expression along the thalamic axon
As a precedent from another system, bcatenin mRNA is found in migrating astrocytic filopodia and hippocampal growth cones where its translation in response to the neurotrophic factor NT3 is dependent on the Cytoplasmic Polyadenylation Element-Binding Protein (CPEBP) binding to discrete elements in its 3’UTR [72,73]
Summary
The mammalian thalamus relays sensory information from the periphery to the cerebral cortex for cognitive processing via the thalamocortical tract. In this study we tested whether b-catenin is likely to play a role in thalamocortical connectivity by examining its expression and activity in developing thalamic neurons and their axons. Thalamic nuclei form precise reciprocal connections with their targets in the cerebral cortex providing it with most of its sensory innervation via thalamocortical axons. Wnt signalling components are expressed in complex patterns in the developing thalamus itself and in the territory encountered by thalamocortical axons. The thalamus is unique within the adult CNS in having sufficiently high levels of nuclear b-catenin to be detectable with immunohistochemistry and b-catenin mediated TCF/LEF transcription plays a key role in defining the electrophysiological properties of thalamic cells [36,37]. While the manipulation of b-catenin activity has provided insights into the function of b-catenin in neural progenitor cells there are as yet no tractable transgenic models which allow the role of b-catenin to be studied in post-mitotic neurons [38,39,40,41,42,43]
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