ABSTRACT
The Wnt/ß-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/ß-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/ß-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior.
ABSTRACT
Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were 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 a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in 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 control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.
Subject(s)
Cell Differentiation , Gene Expression Regulation, Developmental , Mitosis , Synaptic Transmission , Thalamus/embryology , Transcription Factor 4/metabolism , Animals , Mice , Mice, Knockout , Thalamus/cytology , Transcription Factor 4/geneticsABSTRACT
The thalamus is a major part of the diencephalon and a hub for integrating sensory, motor and emotional information. Thalamocortical neuronal loops are involved in processing of sensory stimuli, directing attention, regulating the level of conscious awareness and selecting behavioural responses. The establishment of topographic thalamo-cortical connections is critical for brain performance, and their dysfunctions can contribute to the development of mental disorders. Thalamic axon guidance is regulated by the expression of molecular cues along the way to the cortex. In this review we outline the guiding process from the early growth of thalamic axons to their topographic targeting to specific cortical areas.
