TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

Abstract

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. AbstractNeuronal 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.of the mice colony, and Kacper Posyniak for assistance with sample staining and acquisition.

Thalamo-Habenular Connection Differences Between Patients With Major Depressive Disorder and Normal Controls

“…In a resting state fMRI study, the habenula showed significant connectivity with the thalamus; however, the authors did not report differential connectivity in this tract between participants with low and high subclinical depression scores (46). Animal studies using mice reported that the TCF7L2 gene, known as a risk factor for schizophrenia and autism (47), affected the connectivity and cell clustering of the thalamo-habenular region (48). Since this is a cross-sectional study, we are unable to determine the cause of the higher number of right habenula-left mediodorsal thalamus tracts in patients with MDD than in NCs.…”

Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

“…The unique patterns of transcription factor activities might also regulate the development of patterning and connectivity of the MHb and LHb (Quina et al, 2009). Recently, Lipiec et al (2019) found that transcription factor Tcf7l2 regulates the development of anatomical segregations and axonal patterns of the habenula through Tcf7l2 knockout assays, whereas Tcf7l2 also regulates nicotine sensitivity and nAChR function in the MHb in adult rodents (Duncan et al, 2019). Consistent with their findings, our SCENIC analysis showed that Tcf7l2 regulates a variety of DEGs, including ion channels, neurotransmission, and cytoskeleton-related genes in the MHb and the LHb.…”

Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

“…In addition to cellular properties in the adult habenula, the unique patterns of transcription factor activities might regulate the development of patterning and connectivity of the MHb and LHb (Quina et al, 2009). Recently, Lipiec et al found that transcription factor Tcf7l2 regulates the development of anatomical segregations and axonal patterns of the habenula through Tcf7l2 knockout assays (Lipiec et al, 2019). Consistent with their findings, our SCENIC analysis showed that Tcf7l2 regulates a variety of DEGs including ion channels, neurotransmission and cytoskeleton related genes in the MHb and the LHb (Figure S3).…”