Cystatin B is essential for proliferation and interneuron migration in individuals with EPM1 epilepsy.
EPM1
cystatin B
interneuron migration
neurogenesis
secretion
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 06 2020
08 06 2020
Historique:
received:
09
09
2019
revised:
01
04
2020
accepted:
02
04
2020
pubmed:
8
5
2020
medline:
19
8
2021
entrez:
8
5
2020
Statut:
ppublish
Résumé
Progressive myoclonus epilepsy (PME) of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder with the highest incidence of PME worldwide. Mutations in the gene encoding cystatin B (CSTB) are the primary genetic cause of EPM1. Here, we investigate the role of CSTB during neurogenesis in vivo in the developing mouse brain and in vitro 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' proliferation and modulates neuronal distribution by attracting interneurons to the site of secretion via cell-non-autonomous mechanisms. Similarly, in patient-derived 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' hCOs. Overall, our study sheds new light on the cellular mechanisms underlying the development of EPM1.
Identifiants
pubmed: 32378798
doi: 10.15252/emmm.201911419
pmc: PMC7278547
doi:
Substances chimiques
CSTB protein, human
0
Cstb protein, mouse
0
Cystatin B
88844-95-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e11419Subventions
Organisme : Max Planck Society
Pays : International
Organisme : University of Naples Federico II
Pays : International
Organisme : Finanziamento Ricerca di Ateneo
Pays : International
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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