{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:53:24Z","timestamp":1788947604280,"version":"build-2803163510"},"posted":{"date-parts":[[2025,12,9]]},"group-title":"Neuroscience","reference-count":93,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital"},{"id":[{"id":"https:\/\/ror.org\/0215cks11","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>DEPDC5<\/jats:italic>\n                  (DEP domain-containing protein 5) encodes a repressor of the mTORC1 signaling pathway. Variants in\n                  <jats:italic>DEPDC5<\/jats:italic>\n                  are associated with a range of focal epilepsies, including mosaic variants associated with focal cortical dysplasia (FCD) and other focal brain malformations with brain-only somatic mosaic variants. To investigate the role of\n                  <jats:italic>DEPDC5<\/jats:italic>\n                  in human epilepsy related to mosaic variants, we have generated mosaic\n                  <jats:italic>depdc5<\/jats:italic>\n                  loss-of-function zebrafish models using homology-based constructs acutely targeting\n                  <jats:italic>depdc5<\/jats:italic>\n                  and labeled with tdTomato to allow for visualization of the degree of mosaicism. The resulting mosaic\n                  <jats:italic>depdc5<\/jats:italic>\n                  CRISPants demonstrated early larval death, with \u223c50% of CRISPants (vs. 10% of controls) dead by 7 days post fertilization (dpf), analogous to the early death sometimes associated with human\n                  <jats:italic>DEPDC5<\/jats:italic>\n                  -related epilepsy. We compared\n                  <jats:italic>depdc5<\/jats:italic>\n                  CRISPants with uninjected and scrambled controls from the same clutches. Body and head size were reduced in the\n                  <jats:italic>depdc5<\/jats:italic>\n                  CRISPants. Analysis of swimming behavior showed a striking reduction in distance traveled and maximum velocity in the\n                  <jats:italic>depdc5<\/jats:italic>\n                  CRISPants vs. controls. Based on visual confirmation of mutational load, we categorized CRISPants into\n                  <jats:italic>depdc5<\/jats:italic>\n                  + vs. depdc5++, reflecting weak vs. strong tdTomato fluorescence. We observed that\n                  <jats:italic>depdc5<\/jats:italic>\n                  ++ CRISPants had increased episodes of posture loss, suggesting increased seizure-like behavior related to higher percentages of mutant cells. Local field potential recordings revealed increased neuronal hyperexcitability in\n                  <jats:italic>depdc5<\/jats:italic>\n                  CRISPants vs. controls. Acridine orange staining demonstrated early apoptosis in the CRISPants vs. controls. Our mosaic\n                  <jats:italic>depdc5<\/jats:italic>\n                  CRISPants provide a clinically relevant model to study the role of mosaic DEPDC5-related epilepsy and early death.\n                <\/jats:p>","DOI":"10.64898\/2025.12.04.692362","type":"posted-content","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T19:15:35Z","timestamp":1765307735000},"source":"Crossref","is-referenced-by-count":1,"title":["Early death and neuronal abnormalities in\n                  <i>depdc5<\/i>\n                  loss-of-function mosaic zebrafish models"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-4153","authenticated-orcid":false,"given":"Sneham","family":"Tiwari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4377-1560","authenticated-orcid":false,"given":"Christopher M.","family":"LaCoursiere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3995-4341","authenticated-orcid":false,"given":"Hyun Yong","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8350-7039","authenticated-orcid":false,"given":"Joseph","family":"Pascucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5181-6515","authenticated-orcid":false,"given":"Parul","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-3699","authenticated-orcid":false,"given":"Richard 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