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Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    in the developing mouse brain and\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    in human cerebral organoids (hCOs) derived from EPM1 patients. We find that CSTB (but not one of its pathological variants) is secreted into the mouse cerebral spinal fluid and the conditioned media from hCOs. In embryonic mouse brain, we find that functional CSTB influences progenitors\u2019 proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell\u2010non\u2010autonomous mechanisms. Similarly, in patient\u2010derived hCOs, low levels of functional CSTB result in an alteration of progenitor's proliferation, premature differentiation, and changes in interneurons migration. Secretion and extracellular matrix organization are the biological processes particularly affected as suggested by a proteomic analysis in patients\u2019 hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201911419","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T06:05:30Z","timestamp":1588831530000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy"],"prefix":"10.1038","volume":"12","author":[{"given":"Francesco","family":"Di Matteo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizia","family":"Pipicelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Kyrousi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Tovecci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Penna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Crispino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Chambery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosita","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane Cristina","family":"Ayo\u2010Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Ciusani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Canafoglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1551-9203","authenticated-orcid":false,"given":"Magdalena","family":"G\u00f6tz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3604-3697","authenticated-orcid":false,"given":"Rossella","family":"Di Giaimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-9038","authenticated-orcid":false,"given":"Silvia","family":"Cappello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,7]]},"reference":[{"key":"BFEMMM201911419_CR1","doi-asserted-by":"crossref","first-page":"541","DOI":"10.24953\/turkjped.2016.05.014","volume":"58","author":"S Aka","year":"2016","unstructured":"Aka S, Alanay Y, Boodhansingh KE, Stanley CA, Semiz S (2016) Seizures and diagnostic difficulties in hyperinsulinism\u2010hyperammonemia syndrome. 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