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A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice

The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neuro...

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Autores principales: Brugmans, Aliska K., Walter, Carolin, Moreno, Natalia, Göbel, Carolin, Holdhof, Dörthe, de Faria, Flavia W., Hotfilder, Marc, Jeising, Daniela, Frühwald, Michael C., Skryabin, Boris V., Rozhdestvensky, Timofey S., Wachsmuth, Lydia, Faber, Cornelius, Dugas, Martin, Varghese, Julian, Schüller, Ulrich, Albert, Thomas K., Kerl, Kornelius
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477118/
https://www.ncbi.nlm.nih.gov/pubmed/37219662
http://dx.doi.org/10.1007/s10571-023-01361-5
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author Brugmans, Aliska K.
Walter, Carolin
Moreno, Natalia
Göbel, Carolin
Holdhof, Dörthe
de Faria, Flavia W.
Hotfilder, Marc
Jeising, Daniela
Frühwald, Michael C.
Skryabin, Boris V.
Rozhdestvensky, Timofey S.
Wachsmuth, Lydia
Faber, Cornelius
Dugas, Martin
Varghese, Julian
Schüller, Ulrich
Albert, Thomas K.
Kerl, Kornelius
author_facet Brugmans, Aliska K.
Walter, Carolin
Moreno, Natalia
Göbel, Carolin
Holdhof, Dörthe
de Faria, Flavia W.
Hotfilder, Marc
Jeising, Daniela
Frühwald, Michael C.
Skryabin, Boris V.
Rozhdestvensky, Timofey S.
Wachsmuth, Lydia
Faber, Cornelius
Dugas, Martin
Varghese, Julian
Schüller, Ulrich
Albert, Thomas K.
Kerl, Kornelius
author_sort Brugmans, Aliska K.
collection PubMed
description The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb1(1148del/1148del) mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10571-023-01361-5.
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spelling pubmed-104771182023-09-06 A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice Brugmans, Aliska K. Walter, Carolin Moreno, Natalia Göbel, Carolin Holdhof, Dörthe de Faria, Flavia W. Hotfilder, Marc Jeising, Daniela Frühwald, Michael C. Skryabin, Boris V. Rozhdestvensky, Timofey S. Wachsmuth, Lydia Faber, Cornelius Dugas, Martin Varghese, Julian Schüller, Ulrich Albert, Thomas K. Kerl, Kornelius Cell Mol Neurobiol Original Research The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb1(1148del/1148del) mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10571-023-01361-5. Springer US 2023-05-23 2023 /pmc/articles/PMC10477118/ /pubmed/37219662 http://dx.doi.org/10.1007/s10571-023-01361-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Research
Brugmans, Aliska K.
Walter, Carolin
Moreno, Natalia
Göbel, Carolin
Holdhof, Dörthe
de Faria, Flavia W.
Hotfilder, Marc
Jeising, Daniela
Frühwald, Michael C.
Skryabin, Boris V.
Rozhdestvensky, Timofey S.
Wachsmuth, Lydia
Faber, Cornelius
Dugas, Martin
Varghese, Julian
Schüller, Ulrich
Albert, Thomas K.
Kerl, Kornelius
A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice
title A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice
title_full A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice
title_fullStr A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice
title_full_unstemmed A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice
title_short A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice
title_sort carboxy-terminal smarcb1 point mutation induces hydrocephalus formation and affects ap-1 and neuronal signalling pathways in mice
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477118/
https://www.ncbi.nlm.nih.gov/pubmed/37219662
http://dx.doi.org/10.1007/s10571-023-01361-5
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