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

2023; American Association for the Advancement of Science; Volume: 380; Issue: 6651 Linguagem: Inglês

10.1126/science.adf8440

1095-9203

Lea Kiefer, Anna Chiosso, Jennifer Langen, Alex R. Buckley, Simon Gaudin, Sandy M. Rajkumar, Gabrielle Isabelle F. Servito, S. Elizabeth, Akshara Vijay, Albert Yeung, Adan Horta, Michael H. Mui, Daniele Canzio,

Wnt/β-catenin signaling in development and cancer

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 depend on the activity of cohesin and its unloader, WAPL (wings apart-like protein homolog). While cohesin erases genomic-distance biases in Pcdh choice, WAPL functions as a rheostat of cohesin processivity that determines Pcdh isoform diversity.