Biology subjects

Lipiec, M. A.

Publications and source records attributed to Lipiec, M. A..

4 recordsLinked to original sources

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↗

bioRxiv2020

β-catenin signaling via astrocyte-encoded TCF7L2 regulates neuronal excitability and social behavior

Astrocytes play essential roles in supporting neuronal activity and synapse formation; however, mechanisms by which these functions are regulated are unclear. The Wnt/{beta}-catenin signaling pathway plays a crucial role in brain development and is implicated in neurodevelopmental disorders including autism spectrum disorder (ASD). We sought to investigate if some impacts of Wnt signaling are mediated via astrocytes. Here we show that the canonical Wnt/{beta}-catenin pathway is active in postnatal cortical astrocytes and that its effector, the transcription factor TCF7L2 -is expressed in astrocyte lineage cells during embryonic and postnatal development in both mouse and human. Astrocyte-specific deletion of Tcf7l2 in the early postnatal period led to alterations in astrocyte morphology, membrane depolarization and decreased cortical neuron excitability. Mice with the conditional knockout exhibited increased sociability and social preference in a naturalistic setting. Taken together, these data reveal a key role of astrocytic Wnt signaling in shaping postnatal neuronal development and adult social behavior.

neuroscience↗

bioRxiv2019

The transcription factor TCF7L2 functions as a terminal selector in thalamic and habenular regions of the brain

Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but few examples of such regulators have been provided in vertebrates. TCF7L2 has been identified as a regulator of efferent outgrowth in the thalamus and habenula. We used a complete and conditional knockout of Tcf7l2 in mice to investigate the hypothesis that TCF7L2 plays a dual role in thalamic neuron differentiation and functions as a terminal selector. Connectivity and cell clustering was disrupted in the thalamo-habenular region in Tcf7l2-/- embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with postnatal Tcf7l2 knockout, the induction of genes that confer terminal electrophysiological features of thalamic neurons was impaired. Many of these genes proved to be TCF7L2 direct targets. The role of TCF7L2 in thalamic terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that maintain regional transcriptional network, control stage-specific genetic programs and induce terminal selection. StatementThe study describes a role of TCF7L2 in neuronal differentiation of thalamic glutamatergic neurons at two developmental stages, highlighting its involvement in the postnatal establishment of critical thalamic electrophysiological features.

developmental biology↗