Tcf4 encodescortical differentiation during development

Abstract

Tcf4 has been linked to autism, schizophrenia, and Pitt-Hopkins Syndrome (PTHS) in humans, however, the mechanisms behind its role in disease development is still elusive. In the present study, we provide evidence that Tcf4 has a critical function in the differentiation of cortical regions during development.We show that Tcf4 is present throughout the developing brain at the peak of neurogenesis. Deletion of Tcf4 results in mis-specification of the cortical layers, malformation of the corpus callosum and hypoplasia of the hippocampus. 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 the emergence of other neurodevelopmental disorders. Taken together, we show that neurogenesis and differentiation are severely affected in Tcf4 mutants, phenocopying morphological brain defects detected in PTHS patients. The presented data identifies new leads to understand the mechanism of human brain defects and will assist in genetic counseling programs.show aberrant co-localization with SATB2. Besides these differentiation defects, the corpus callosum and both hippocampi are severely underdeveloped in these mutants. Transcriptome analyzes through RNA-sequencing on E14.5 cortical material indicate that Tcf4 is an activator of gene expression in the developing cortex and is activates genes that are linked to neurogenesis and neuronal maturation. Importantly, Tcf4 regulates genes that are known for their involvement in clinical syndromes related to PTHS and ID. Finally, the observed brain malformations phenocopy clinical features observed in PTHS patients, further establishing this mouse mutant as an excellent model for this human developmental disorder, providing mechanistic insight to the syndrome and assist in the identification of novel factors for genetic screening and genetic counseling for human patients with neurodevelopmental disorders.