Figure 3. Control of synapse specification by alternative splicing programs.
a) Schematic illustrating the control of alternative splicing by RNA motifs and trans-acting factors (coloured spheres X1, X2, X3…). The displayed alternatively spliced segment contains an alternative splice donor site in the upstream exon (depicted as grey and blue boxes on left), followed by a cassette exon (purple box) and a downstream constitutive exon (grey box, right). Exons can contain exonic splicing enhancers (ESE) and exonic splicing silencers (ESS). The intronic between the exon boxes contain RNA motifs that act as intronic splicing enhancers (ISE) and silencers (ISS). GU marks the 5’ splice site, A-Py-AG marks the branchpoint and Polypyrimidine tract followed by the terminal AG sequence in the intron. Motifs recruit trans-acting RNA-binding proteins (depicted as colored spheres) which either promote or suppress usage of individual splice donor acceptor sites, resulting in inclusion or skipping of the alternative cassette exon (isoform 1 and isoform 2). Usage of the alternative donor site in the first exon, results in a third transcript isoform (isoform3).
b) Intersection of Nrxn transcriptional programs and the combinatorial action of splicing regulators. The illustration depicts two hypothetical cell types (cell type 1 and cell type 2) that produce different Neurexin transcript repertoires. Cell type-specific transcription from promoters/enhancers (arrowheads) drives the differential transcription of the primary transcripts from the Nrxn genes (e.g. Cell type 1 transcribes high levels of NRXN1α whereas Cell type 2 transcribes high levels of NRXN3α). In addition, each expresses a specific battery of splicing regulators (Cell type 1: X1,X2, X3,…; Cell type 2: X1, X3, X5,…). The intersection of these splicing regulators (colored spheres) with the primary Nrxn transcripts then produces the cell type-specific Neurexin isoforms (e.g. β Nrxn AS4-AS5- in cell type 1 and β Nrxn AS4+AS5+ in cell type 2) 76,79,89 .