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ScRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse

ABSTRACT: The bHLH transcription factor TCF4 plays an important role in neurodevelopment highlighted by its association with schizophrenia and Pitt-Hopkins-Syndrome. Here we demonstrate that TCF4 function is essential for forebrain commissure formation in mice. Single-cell RNA sequencing of TCF4 knockout neocortices revealed dysregulation of multiple gene regulatory networks. We provide evidence that TCF4 controls the underlying regulons by interaction with the regulators, transcription factors surprisingly not belonging to the known canonical interactors of the bHLH family. In-depth analysis of the interplay between TCF4 and SOX11 showed a synergistic effect on commissural formation. Mice haploinsufficient for Sox11 or Tcf4 showed no commissural phenotype or only a mild callosal shortening, respectively, whereas Tcf4/Sox11 double haploinsufficient mice display aggravated corpus callosum dysgenesis and anterior commissure agenesis. Moreover, TCF4 and SOX11 synergistically induce the expression of common target genes. Collectively, these findings illuminate how TCF4 dysregulation influences brain development and contributes to neurodevelopmental diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE147247 | GEO | 2021/07/04

REPOSITORIES: GEO

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