Gabriel, M. O. | bioRxiv Science

bioRxiv2025

β-catenin-independent regulation by TCF7L2 underlies isoform redundancy during embryonic thalamic development

Alternative promoter usage generates multiple transcription factor isoforms during brain development, yet their functional significance remains poorly defined. One such example is TCF7L2, a transcription factor critical for the development of the thalamus and recurrently affected by de novo mutations in autism spectrum disorder. TCF7L2 exists in two isoforms driven from different promoters: the long isoform (L-TCF7L2) with the {beta}-catenin-binding domain, and the shorter isoform (S-TCF7L2), lacking this domain and classically considered a dominant-negative regulator of the L isoform. We investigated the role of TCF7L2 isoforms in thalamic development using total and isoform-specific knockout strategies. Integrated phenotypic and transcriptomic analyses revealed functional redundancy of TCF7L2 isoforms during embryogenesis. {beta}-catenin subcellular localization and chromatin occupancy uncovered a developmental switch in TCF7L2 activity, from a {beta}-catenin-independent and isoform-redundant mode in the embryonic thalamus to a {beta}-catenin-dependent program postnatally. More broadly, these findings point to distinct embryonic and postnatal regulatory strategies, with alternative promoter usage potentially supporting robust availability of regulatory proteins during brain development.

neuroscience↗

bioRxiv2025

The Role of TCF7L2 in Regulating Energy Metabolism in Thalamocortical Circuitry and its Broader Impact on Social Behavior

Psychiatric and metabolic disorders often co-occur. While shared genetic factors and cellular dysfunctions are implicated, the underlying molecular mechanisms remain poorly understood. TCF7L2, a risk gene for type 2 diabetes and autism spectrum disorder, is highly expressed in the thalamus--a brain region extensively interconnected with the cortex, playing a key role in sensory processing, motor control, and behavioral regulation. Given its known role as a transcription factor regulating systemic energy metabolism, we explored its potential contribution to brain metabolism and behavior. To this end, we used a conditional knockout model with postnatal TCF7L2 loss in the thalamus and partial deficiency in the pancreas. Tcf7l2 knockout mice exhibited social deficits and reduced motor habituation. In parallel, they also developed systemic glucose intolerance, modelling the psychiatric-metabolic comorbidity. Thalamic depletion of TCF7L2 resulted in elevated inhibitory phosphorylation of the pyruvate dehydrogenase --an enzymatic gatekeeper for pyruvate utilization in energy production--in the thalamus and cortex. This was accompanied by altered thalamic and cortical metabolism, characterized by reduced efficiency of pyruvate oxidation alongside enhanced oxidation of fatty acids and ketone bodies. Notably, a ketogenic diet alleviated metabolic dysregulation in the brain and normalized some social behaviors in knockout mice. These findings suggest that impaired energy metabolism in the thalamocortical circuitry may represent one of the pathogenic mechanisms underlying neuropsychiatric symptoms.

neuroscience↗