WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring

Neural-type specific expression of clustered Protocadherin (Pcdh) proteins is essential for the establishment of connectivity patterns during brain development. In mammals, deterministic expression of the same Pcdh isoform promotes minimal overlap of tiled projections of serotonergic neuron axons throughout the brain, while stochastic expression of Pcdh genes allows for convergence of tightly packed overlapping olfactory sensory neuron axons into targeted structures. How can the same gene locus generate opposite transcriptional programs that orchestrate distinct spatial arrangements of axonal patterns? Here, we reveal that cell-type specific Pcdh expression and axonal behavior rest on the activity of cohesin and its unloader WAPL. While cohesin erases genomic-distance biases in Pcdh choice, WAPL functions as a rheostat of cohesin processivity that determines Pcdh isoform diversity. Overall design: Examination of RNA and genome folding within the clustered Protocadherin locus in olfactory sensory neurons, the olfactory epithilium, and the Raphe from mice carrying genetic mutations.