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

Alternative splicing is a key regulatory process underlying\r\nthe amplification of genomic information\r\nand the expansion of proteomic diversity, particularly\r\nin brain. Here, we identify the Ewing sarcoma\r\nprotein (EWS) as a new player of alternative splicing\r\nregulation during neuronal differentiation. Knockdown\r\nof EWS in neuronal progenitor cells leads to\r\npremature differentiation. Transcriptome profiling of\r\nEWS-depleted cells revealed global changes in splicing\r\nregulation. Bioinformatic analyses and biochemical\r\nexperiments demonstrated that EWS regulates\r\nalternative exons in a position-dependent fashion.\r\nNotably, several EWS-regulated splicing events are\r\nphysiologically modulated during neuronal differentiation\r\nand EWS depletion in neuronal precursors\r\nanticipates the splicing-pattern of mature neurons.\r\nAmong other targets, we found that EWS controls the\r\nalternative splicing of the forkhead family transcription\r\nfactor FOXP1, a pivotal transcriptional regulator\r\nof neuronal differentiation, possibly contributing to\r\nthe switch of gene expression underlying the neuronal\r\ndifferentiation program.