Model for coregulation of microexons by SRRM4 and PRPF40A. For conventional-sized exons, splicing proceeds via exon definition, in which the unit of recognition is the exon. This is not physically feasible for microexons, which cannot accommodate the binding of both the U1 and U2 snRNPs on such a small sequence space. However, in our model, this physical constraint can be overcome when SRRM4, binding to UGC-containing motifs in the flanking intron, interacts with PRPF40A, which then facilitates splicing either through a novel exon-definition mechanism, or alternatively by an intron-spanning intron definition process. Either mechanism overcomes the failure to splice according to standard exon definition mechanisms, and the result is microexon inclusion in the mature mRNA.
