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Through structure and function studies, we identified a WW-binding motif within the NL2 intracellular domain required for astrocyte morphogenesis. Using cell-specific in vivo proximity labeling (iBioID), we found that each NL displays distinct protein\u2013protein interactions within astrocytes, distinct from the neuronal NL2-binding partners. From these data, we identified a role for WW domain\u2013containing E3 ubiquitin ligase Nedd4l in astrocyte morphogenesis. Biochemical assays revealed Nedd4l ubiquitinates and stabilizes NL2, and this ubiquitination is required for astrocyte morphogenesis. This study shows that NLs have nonoverlapping roles in controlling astrocyte growth and uncovers a molecular mechanism of how NL2 mediates astrocyte morphogenesis.<\/jats:p>","DOI":"10.1083\/jcb.202512111","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T06:21:22Z","timestamp":1777530082000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Neuroligin-2 is ubiquitinated by Nedd4l to control developmental astrocyte morphogenesis"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8853-053X","authenticated-orcid":true,"given":"Kristina","family":"Sakers","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 1 Department of Cell Biology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Howard Hughes Medical Institute, Duke University Medical Center 2 , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5724-6384","authenticated-orcid":true,"given":"Juan J.","family":"Ramirez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 1 Department of Cell Biology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 4 Department of Neurobiology, , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5686-0666","authenticated-orcid":true,"given":"Nimrod","family":"Elazar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 1 Department of Cell Biology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Howard Hughes Medical Institute, Duke University Medical Center 2 , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5405-7595","authenticated-orcid":true,"given":"Leykashree","family":"Nagendren","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 1 Department of Cell Biology, , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6765-1786","authenticated-orcid":true,"given":"Erik","family":"Soderblom","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 1 Department of Cell Biology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"3 Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7204-0218","authenticated-orcid":true,"given":"Cagla","family":"Eroglu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 1 Department of Cell Biology, , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Howard Hughes Medical Institute, Duke University Medical Center 2 , Durham, NC,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03njmea73","id-type":"ROR","asserted-by":"publisher"}],"name":"Duke University Medical Center 4 Department of Neurobiology, , Durham, NC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"2026060109190048400_bib1","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s41586-021-03441-2","article-title":"Astrocytes close a motor circuit critical period","volume":"592","author":"Ackerman","year":"2021","journal-title":"Nature"},{"key":"2026060109190048400_bib2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201902050","article-title":"Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity","volume":"223","author":"Altas","year":"2024","journal-title":"J. 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