Abstract
Tcf4 has been linked to autism, schizophrenia, and Pitt-Hopkins Syndrome (PTHS) in humans, suggesting a role for Tcf4 in brain development and importantly cortical development. However, the mechanisms behind its role in disease and brain development are still elusive. We provide evidence that Tcf4 has a critical function in the differentiation of cortical regions, corpus callosum and anterior commissure formation, and development of the hippocampus during murine embryonic development.In the present study, we show that Tcf4 is expressed throughout the developing brain at the peak of neurogenesis. Deletion of Tcf4 results in mis-specification of the cortical neurons, malformation of the corpus callosum and anterior commissure, and hypoplasia of the hippocampus. Furthermore, the Tcf4 mutant shows an absence of midline remodeling, underlined by the loss of GFAP-expressing midline glia in the indusium griseum and callosal wedge and midline zipper glia in the telencephalic midline. RNA-sequencing on E14.5 cortex material shows that Tcf4 functions as a transcriptional activator and loss of Tcf4 results in downregulation of genes linked to neurogenesis and neuronal maturation. Furthermore, many genes that are differentially expressed after Tcf4 ablation are linked to other neurodevelopmental disorders. Taken together, we show that correct brain development and neuronal differentiation are severely affected in Tcf4 mutants, phenocopying morphological brain defects detected in PTHS patients. The presented data identifies new leads to understand the mechanisms behind brain and specifically cortical development and can provide novel insights in developmental mechanisms underlying human brain defects.
Highlights
Correct brain development depends on a complex genetic program executed through strongly regulated spatio-temporal expression of transcription factors
At E14.5 Tcf4 transcript is detected throughout the developing brain, it is most abundantly expressed in the neocortex, with a strong expression in the cortical plate (CP)
We have shown that Tcf4 is expressed throughout the brain, with specific expression in different layers of the murine neocortex during development, and that it has a central role in brain development
Summary
Correct brain development depends on a complex genetic program executed through strongly regulated spatio-temporal expression of transcription factors. A specific group of transcription factors linked to brain development is the basic helix-loop-helix (bHLH) protein family (Powell and Jarman, 2008). E-box proteins have mainly been studied in relation to their role in immune system development. They are found to be critical for the transition from CD4+CD8+ double-positive T-cells to CD4+ or CD8+ single-positive T-cells (Wojciechowski et al, 2007) and loss of either Tcf or Tcf leads to an early depletion of T-cell progenitors and a decrease in mature T-cells (Wojciechowski et al, 2007). On the other hand, has only a minor role during early thymocyte development and it has been suggested that compensatory mechanisms through Tcf and/or Tcf exist (Wikström et al, 2008)
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