NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome

BACKGROUND: Fragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differenti...

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Autores principales: Kurosaki, Tatsuaki, Sakano, Hitomi, Pröschel, Christoph, Wheeler, Jason, Hewko, Alexander, Maquat, Lynne E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Short Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597091/
https://www.ncbi.nlm.nih.gov/pubmed/34784943
http://dx.doi.org/10.1186/s13059-021-02530-9
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author Kurosaki, Tatsuaki
Sakano, Hitomi
Pröschel, Christoph
Wheeler, Jason
Hewko, Alexander
Maquat, Lynne E.
author_facet Kurosaki, Tatsuaki
Sakano, Hitomi
Pröschel, Christoph
Wheeler, Jason
Hewko, Alexander
Maquat, Lynne E.
author_sort Kurosaki, Tatsuaki
collection PubMed
description BACKGROUND: Fragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differentiation in human stem cells. RESULTS: We show here that NMD is hyperactivated during the development of the cerebral cortex, hippocampus, and cerebellum in the Fmr1-knockout (KO) mouse during embryonic and early postnatal periods. Our findings demonstrate that NMD regulates many neuronal mRNAs that are important for mouse brain development. CONCLUSIONS: We reveal the abnormal regulation of these mRNAs in the Fmr1-KO mouse, a model of FXS, and highlight the importance of early intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02530-9.
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spelling pubmed-85970912021-11-17 NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome Kurosaki, Tatsuaki Sakano, Hitomi Pröschel, Christoph Wheeler, Jason Hewko, Alexander Maquat, Lynne E. Genome Biol Short Report BACKGROUND: Fragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differentiation in human stem cells. RESULTS: We show here that NMD is hyperactivated during the development of the cerebral cortex, hippocampus, and cerebellum in the Fmr1-knockout (KO) mouse during embryonic and early postnatal periods. Our findings demonstrate that NMD regulates many neuronal mRNAs that are important for mouse brain development. CONCLUSIONS: We reveal the abnormal regulation of these mRNAs in the Fmr1-KO mouse, a model of FXS, and highlight the importance of early intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02530-9. BioMed Central 2021-11-16 /pmc/articles/PMC8597091/ /pubmed/34784943 http://dx.doi.org/10.1186/s13059-021-02530-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Short Report
Kurosaki, Tatsuaki
Sakano, Hitomi
Pröschel, Christoph
Wheeler, Jason
Hewko, Alexander
Maquat, Lynne E.
NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome
title NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome
title_full NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome
title_fullStr NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome
title_full_unstemmed NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome
title_short NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome
title_sort nmd abnormalities during brain development in the fmr1-knockout mouse model of fragile x syndrome
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597091/
https://www.ncbi.nlm.nih.gov/pubmed/34784943
http://dx.doi.org/10.1186/s13059-021-02530-9
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