NFIB and TCF4 converge to regulate the expression of genes involved in neuronal differentiation during neocortical development

NFIB or TCF4 haploinsufficiency results in distinct neurodevelopmental disorders that share several characteristic overlapping features. Recent studies suggest that these transcription factors converge by binding to the same cis-regulatory elements and thereby regulate a common set of target genes. Here, we sought to determine whether in mice, NFIB and TCF4 converge during neocortical development. NFIB and TCF4 are co-expressed in radial glial cells and postmitotic neurons. Transcriptomic analyses of Nfib and Tcf4 knockout mice uncovered an overlapping set of downregulated genes involved in neuronal differentiation. Analyses of genome-wide binding further demonstrate that NFIB and TCF4 largely bind to the same regulatory elements. In luciferase assays, NFIB and TCF4 elicit distinct effects on transcriptional activity that differ between the regulatory elements and cell types that we tested. We propose that this heterogeneity is a means through which NFIB and TCF4 function cooperatively to fine-tune target gene expression. Our study provides critical evidence for the molecular convergence of NFIB and TCF4. This indicates that the human syndromes resulting from mutations in these genes may have overlapping underlying etiologies.