INTRODUCTION: The thalamus integrates sensory information and is involved in the selection of behavioral responses. This requires proper development of thalamic nuclei, thalamocortical connections, and electrophysiological properties of thalamic neurons. Molecular mechanisms of postmitotic thalamic differentiation and adult homeostasis were poorly characterized. Our studies show that both are regulated by the transcription factor TCF7L2. AIM(S): To determine the role of TCF7L2 in the development of thalamic cytoarchitecture, molecular anatomy, thalamocortical connections, and intrinsic excitability of thalamic neurons. METHOD(S): We examined mouse embryos (E18.5) with a total knockout of Tcf7l2, and adolescent/adult mice (P20‑P60) with thalamus‑specific, postnatal knockout of Tcf7l2. Embryonic brain slices were used for Nissl staining to visualize anatomical structures, in situ hybridization for gene expression analysis, immunohistochemistry to visualize axon fibers and diencephalic substructures, or thalamocortical neural tracts tracing with DiI. Comparative RNA‑seq analysis was performed on isolates from thalami of both mouse strains. Live brain slices from adolescent TCF7L2-deficent mice were used for in vitro patch‑clamp analysis of thalamic neurons. RESULTS: E18.5 Tcf7l2‑/‑ mice show changes in anatomical and molecular boundaries in diencephalon, fail to produce thalamocortical axons, and do not maintain the expression of main transcription factors that mark thalamic subregions. Postnatal TCF7L2‑deficent thalamic neurons show reduced burst and tonic spiking. CONCLUSIONS: Accordingly, RNA‑seq study revealed changes in the expression of their typical ion channels. TCF7L2 orchestrates a network of transcription factor genes to regulate postmitotic molecular differentiation, segregation of neurons, and axon path-finding in the thalamo‑habenular domain. Continuous expression of TCF7L2 in adult is required to establish proper intrinsic electrophysiological properties of thalamic neurons.
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