EWS splicing regulation contributes to balancing Foxp1 isoforms required for neuronal differentiation

Alternative splicing is a key regulatory process underlying the amplification of genomic information and the expansion of proteomic diversity, particularly in brain. Here, we identify the Ewing sarcoma protein (EWS) as a new player of alternative splicing regulation during neuronal differentiation. Knockdown of EWS in neuronal progenitor cells leads to premature differentiation. Transcriptome profiling of EWS-depleted cells revealed global changes in splicing regulation. Bioinformatic analyses and biochemical experiments demonstrated that EWS regulates alternative exons in a position-dependent fashion. Notably, several EWS-regulated splicing events are physiologically modulated during neuronal differentiation and EWS depletion in neuronal precursors anticipates the splicing-pattern of mature neurons. Among other targets, we found that EWS controls the alternative splicing of the forkhead family transcription factor FOXP1, a pivotal transcriptional regulator of neuronal differentiation, possibly contributing to the switch of gene expression underlying the neuronal differentiation program.

Automated summary

Alternative splicing is a crucial regulatory process for amplifying genomic information and expanding proteomic diversity, particularly in the brain. This study identifies the Ewing sarcoma protein (EWS) as a novel player in alternative splicing regulation during neuronal differentiation. EWS depletion in neuronal progenitor cells leads to premature differentiation and global changes in splicing regulation. EWS controls the alternative splicing of various genes, including the pivotal transcription factor FOXP1, contributing to the switch of gene expression underlying neuronal differentiation.