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Modifying PCDH19 levels affects cortical interneuron migration

PCDH19 is a transmembrane protein and member of the protocadherin family. It is encoded by the X-chromosome and more than 200 mutations have been linked to the neurodevelopmental PCDH-clustering epilepsy (PCDH19-CE) syndrome. A disturbed cell-cell contact that arises when random X-inactivation creat...

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Autores principales: Pancho, Anna, Mitsogiannis, Manuela D., Aerts, Tania, Dalla Vecchia, Marco, Ebert, Lena K., Geenen, Lieve, Noterdaeme, Lut, Vanlaer, Ria, Stulens, Anne, Hulpiau, Paco, Staes, Katrien, Van Roy, Frans, Dedecker, Peter, Schermer, Bernhard, Seuntjens, Eve
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9642031/
https://www.ncbi.nlm.nih.gov/pubmed/36389226
http://dx.doi.org/10.3389/fnins.2022.887478
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author Pancho, Anna
Mitsogiannis, Manuela D.
Aerts, Tania
Dalla Vecchia, Marco
Ebert, Lena K.
Geenen, Lieve
Noterdaeme, Lut
Vanlaer, Ria
Stulens, Anne
Hulpiau, Paco
Staes, Katrien
Van Roy, Frans
Dedecker, Peter
Schermer, Bernhard
Seuntjens, Eve
author_facet Pancho, Anna
Mitsogiannis, Manuela D.
Aerts, Tania
Dalla Vecchia, Marco
Ebert, Lena K.
Geenen, Lieve
Noterdaeme, Lut
Vanlaer, Ria
Stulens, Anne
Hulpiau, Paco
Staes, Katrien
Van Roy, Frans
Dedecker, Peter
Schermer, Bernhard
Seuntjens, Eve
author_sort Pancho, Anna
collection PubMed
description PCDH19 is a transmembrane protein and member of the protocadherin family. It is encoded by the X-chromosome and more than 200 mutations have been linked to the neurodevelopmental PCDH-clustering epilepsy (PCDH19-CE) syndrome. A disturbed cell-cell contact that arises when random X-inactivation creates mosaic absence of PCDH19 has been proposed to cause the syndrome. Several studies have shown roles for PCDH19 in neuronal proliferation, migration, and synapse function, yet most of them have focused on cortical and hippocampal neurons. As epilepsy can also be caused by impaired interneuron migration, we studied the role of PCDH19 in cortical interneurons during embryogenesis. We show that cortical interneuron migration is affected by altering PCDH19 dosage by means of overexpression in brain slices and medial ganglionic eminence (MGE) explants. We also detect subtle defects when PCDH19 expression was reduced in MGE explants, suggesting that the dosage of PCDH19 is important for proper interneuron migration. We confirm this finding in vivo by showing a mild reduction in interneuron migration in heterozygote, but not in homozygote PCDH19 knockout animals. In addition, we provide evidence that subdomains of PCDH19 have a different impact on cell survival and interneuron migration. Intriguingly, we also observed domain-dependent differences in migration of the non-targeted cell population in explants, demonstrating a non-cell-autonomous effect of PCDH19 dosage changes. Overall, our findings suggest new roles for the extracellular and cytoplasmic domains of PCDH19 and support that cortical interneuron migration is dependent on balanced PCDH19 dosage.
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spelling pubmed-96420312022-11-15 Modifying PCDH19 levels affects cortical interneuron migration Pancho, Anna Mitsogiannis, Manuela D. Aerts, Tania Dalla Vecchia, Marco Ebert, Lena K. Geenen, Lieve Noterdaeme, Lut Vanlaer, Ria Stulens, Anne Hulpiau, Paco Staes, Katrien Van Roy, Frans Dedecker, Peter Schermer, Bernhard Seuntjens, Eve Front Neurosci Neuroscience PCDH19 is a transmembrane protein and member of the protocadherin family. It is encoded by the X-chromosome and more than 200 mutations have been linked to the neurodevelopmental PCDH-clustering epilepsy (PCDH19-CE) syndrome. A disturbed cell-cell contact that arises when random X-inactivation creates mosaic absence of PCDH19 has been proposed to cause the syndrome. Several studies have shown roles for PCDH19 in neuronal proliferation, migration, and synapse function, yet most of them have focused on cortical and hippocampal neurons. As epilepsy can also be caused by impaired interneuron migration, we studied the role of PCDH19 in cortical interneurons during embryogenesis. We show that cortical interneuron migration is affected by altering PCDH19 dosage by means of overexpression in brain slices and medial ganglionic eminence (MGE) explants. We also detect subtle defects when PCDH19 expression was reduced in MGE explants, suggesting that the dosage of PCDH19 is important for proper interneuron migration. We confirm this finding in vivo by showing a mild reduction in interneuron migration in heterozygote, but not in homozygote PCDH19 knockout animals. In addition, we provide evidence that subdomains of PCDH19 have a different impact on cell survival and interneuron migration. Intriguingly, we also observed domain-dependent differences in migration of the non-targeted cell population in explants, demonstrating a non-cell-autonomous effect of PCDH19 dosage changes. Overall, our findings suggest new roles for the extracellular and cytoplasmic domains of PCDH19 and support that cortical interneuron migration is dependent on balanced PCDH19 dosage. Frontiers Media S.A. 2022-10-25 /pmc/articles/PMC9642031/ /pubmed/36389226 http://dx.doi.org/10.3389/fnins.2022.887478 Text en Copyright © 2022 Pancho, Mitsogiannis, Aerts, Dalla Vecchia, Ebert, Geenen, Noterdaeme, Vanlaer, Stulens, Hulpiau, Staes, Van Roy, Dedecker, Schermer and Seuntjens. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Pancho, Anna
Mitsogiannis, Manuela D.
Aerts, Tania
Dalla Vecchia, Marco
Ebert, Lena K.
Geenen, Lieve
Noterdaeme, Lut
Vanlaer, Ria
Stulens, Anne
Hulpiau, Paco
Staes, Katrien
Van Roy, Frans
Dedecker, Peter
Schermer, Bernhard
Seuntjens, Eve
Modifying PCDH19 levels affects cortical interneuron migration
title Modifying PCDH19 levels affects cortical interneuron migration
title_full Modifying PCDH19 levels affects cortical interneuron migration
title_fullStr Modifying PCDH19 levels affects cortical interneuron migration
title_full_unstemmed Modifying PCDH19 levels affects cortical interneuron migration
title_short Modifying PCDH19 levels affects cortical interneuron migration
title_sort modifying pcdh19 levels affects cortical interneuron migration
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9642031/
https://www.ncbi.nlm.nih.gov/pubmed/36389226
http://dx.doi.org/10.3389/fnins.2022.887478
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