PMID- 37347873 OWN - NLM STAT- MEDLINE DCOM- 20230710 LR - 20231122 IS - 1095-9203 (Electronic) IS - 0036-8075 (Linking) VI - 380 IP - 6651 DP - 2023 Jun 23 TI - WAPL functions as a rheostat of Protocadherin isoform diversity that controls neural wiring. PG - eadf8440 LID - 10.1126/science.adf8440 [doi] AB - 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. FAU - Kiefer, Lea AU - Kiefer L AUID- ORCID: 0000-0003-2882-4784 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Chiosso, Anna AU - Chiosso A AUID- ORCID: 0000-0002-5778-0429 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Langen, Jennifer AU - Langen J AUID- ORCID: 0000-0003-4427-1489 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Buckley, Alex AU - Buckley A AUID- ORCID: 0000-0003-1975-1106 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Gaudin, Simon AU - Gaudin S AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Ecole Normale Superieure de Lyon, 69432 Lyon, France. FAU - Rajkumar, Sandy M AU - Rajkumar SM AUID- ORCID: 0000-0001-9351-7399 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Servito, Gabrielle Isabelle F AU - Servito GIF AUID- ORCID: 0000-0002-5373-3035 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Cha, Elizabeth S AU - Cha ES AUID- ORCID: 0000-0001-7853-1862 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Vijay, Akshara AU - Vijay A AUID- ORCID: 0000-0002-7369-4256 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Yeung, Albert AU - Yeung A AD - Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. FAU - Horta, Adan AU - Horta A AD - Pura Vida Investments, New York, NY 10106, USA. FAU - Mui, Michael H AU - Mui MH AUID- ORCID: 0000-0003-1985-376X AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Canzio, Daniele AU - Canzio D AUID- ORCID: 0000-0002-2592-2269 AD - Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. AD - Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA. LA - eng PT - Journal Article DEP - 20230623 PL - United States TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (Cadherins) RN - 0 (Protein Isoforms) RN - 0 (Protocadherins) SB - IM MH - Animals MH - Mice MH - Axons/physiology MH - *Brain/growth & development/metabolism MH - *Cadherins/genetics/metabolism MH - Protein Isoforms/genetics/metabolism MH - *Protocadherins/genetics/metabolism MH - *Neurons/metabolism EDAT- 2023/06/22 19:15 MHDA- 2023/06/26 06:41 CRDT- 2023/06/22 14:13 PHST- 2023/06/26 06:41 [medline] PHST- 2023/06/22 19:15 [pubmed] PHST- 2023/06/22 14:13 [entrez] AID - 10.1126/science.adf8440 [doi] PST - ppublish SO - Science. 2023 Jun 23;380(6651):eadf8440. doi: 10.1126/science.adf8440. Epub 2023 Jun 23.