A Phospho-Regulatory Switch Governs the Timing of Cortical Development [scRNA]

Mechanistically, we demonstrate that S265 phosphorylation is a genomic targeting signal that directs Nfib to distal enhancers of key developmental genes. Crucially, residues proximal to the Nfib S265 phosphosite are hotspot for variants in human neurodevelopmental disorders. Our findings establish a model where phosphorylation dictates TF activity to control developmental timing and balance the excitatory and inhibitory neurons at early time points and the glial cell population at later stages, providing critical insights into human brain development and disease.

This integrated analysis enhances our understanding of the molecular foundations of cortical development and highlights the critical role of phosphorylation in regulating TF activity in a stage- and cell-type-specific manner to govern cellular diversity.