DOI: 10.1101/470385Nov 14, 2018Paper

Tcf4 encodes cortical differentiation during development

BioRxiv : the Preprint Server for Biology
Simone MesmanMarten Smidt

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.

Related Concepts

Autistic Disorder
Bone Diseases, Developmental
Brain
Cell Differentiation Process
Cerebral Cortex
Corpus Callosum
Down-Regulation
Gene Deletion
Genes
Genetic Counseling

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