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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Transcription factor 4 (TCF4) is vital for neurodevelopment and implicated in autism, intellectual disability, and schizophrenia.
• TCF4, a class I bHLH TF, was thought to function via dimerization with class II bHLH TFs.

Purpose of the Study:

• To identify Transcription factor 4 (TCF4) partners involved in interhemispheric connectivity.
• To explore TCF4's interactions with non-bHLH TFs in neurodevelopment.

Main Methods:

• Utilized a novel bioinformatic strategy integrating single-cell RNA-sequencing data (scRNA-Seq) for TF expression and regulon activity.
• Investigated TCF4 and SOX11 biochemical interactions and their in vivo role in commissure formation.

Main Results:

• TCF4 interacts with non-bHLH TFs, including FOXG1, SOX11, and BRG1, modulating their activity in Satb2+ neurons.
• TCF4 and SOX11 biochemically interact and cooperatively regulate genes involved in commissure formation.
• Identified a network of TCF4-interacting regulators linked to neurodevelopmental disorder pathogenesis.

Conclusions:

• TCF4 collaborates with non-bHLH TFs in regulating interhemispheric connectivity.
• This study highlights the utility of scRNA-Seq data for predicting TF networks in neurodevelopment.
• Findings offer new insights into the molecular mechanisms underlying neurodevelopmental disorders.