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Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation

Astrocytes are the most abundant cell type within the central nervous system (CNS) with various functions. Furthermore, astrocytes show a regional and developmental heterogeneity traceable with specific markers. In this study, the influence of the low-density lipoprotein receptor-related protein 1 (...

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Autores principales: Romeo, Ramona, Boden-El Mourabit, Damian, Scheller, Anja, Mark, Melanie D., Faissner, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930235/
https://www.ncbi.nlm.nih.gov/pubmed/33679332
http://dx.doi.org/10.3389/fncel.2021.642521
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author Romeo, Ramona
Boden-El Mourabit, Damian
Scheller, Anja
Mark, Melanie D.
Faissner, Andreas
author_facet Romeo, Ramona
Boden-El Mourabit, Damian
Scheller, Anja
Mark, Melanie D.
Faissner, Andreas
author_sort Romeo, Ramona
collection PubMed
description Astrocytes are the most abundant cell type within the central nervous system (CNS) with various functions. Furthermore, astrocytes show a regional and developmental heterogeneity traceable with specific markers. In this study, the influence of the low-density lipoprotein receptor-related protein 1 (LRP1) on astrocytic maturation within the hippocampus was analyzed during development. Previous studies mostly focused on the involvement of LRP1 in the neuronal compartment, where the deletion caused hyperactivity and motor dysfunctions in knockout animals. However, the influence of LRP1 on glia cells is less intensively investigated. Therefore, we used a newly generated mouse model, where LRP1 is specifically deleted from GLAST-positive astrocytes co-localized with the expression of the reporter tdTomato to visualize recombination and knockout events in vivo. The influence of LRP1 on the maturation of hippocampal astrocytes was assessed with immunohistochemical stainings against stage-specific markers as well as on mRNA level with RT-PCR analysis. The examination revealed that the knockout induction caused a significantly decreased number of mature astrocytes at an early developmental timepoint compared to control animals. Additionally, the delayed maturation of astrocytes also caused a reduced activity of neurons within the hippocampus. As previous studies showed that the glial specification and maturation of astrocytes is dependent on the signaling cascades Ras/Raf/MEK/Erk and PI3K/Akt, the phosphorylation of the signaling molecules Erk1/2 and Akt was analyzed. The hippocampal tissue of LRP1-deficient animals at P21 showed a significantly decreased amount of activated Erk in comparison to control tissue leading to the conclusion that the activation of this signaling cascade is dependent on LRP1 in astrocytes, which in turn is necessary for proper maturation of astrocytes. Our results showed that the deletion of LRP1 at an early developmental timepoint caused a delayed maturation of astrocytes in the hippocampus based on an altered activation of the Ras/Raf/MEK/Erk signaling pathway. However, with ongoing development these effects were compensated and the number of mature astrocytes was comparable as well as the activity of neurons. Therefore, LRP1 acts as an early regulator of the differentiation and maturation of astrocytes within the hippocampus.
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spelling pubmed-79302352021-03-05 Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation Romeo, Ramona Boden-El Mourabit, Damian Scheller, Anja Mark, Melanie D. Faissner, Andreas Front Cell Neurosci Neuroscience Astrocytes are the most abundant cell type within the central nervous system (CNS) with various functions. Furthermore, astrocytes show a regional and developmental heterogeneity traceable with specific markers. In this study, the influence of the low-density lipoprotein receptor-related protein 1 (LRP1) on astrocytic maturation within the hippocampus was analyzed during development. Previous studies mostly focused on the involvement of LRP1 in the neuronal compartment, where the deletion caused hyperactivity and motor dysfunctions in knockout animals. However, the influence of LRP1 on glia cells is less intensively investigated. Therefore, we used a newly generated mouse model, where LRP1 is specifically deleted from GLAST-positive astrocytes co-localized with the expression of the reporter tdTomato to visualize recombination and knockout events in vivo. The influence of LRP1 on the maturation of hippocampal astrocytes was assessed with immunohistochemical stainings against stage-specific markers as well as on mRNA level with RT-PCR analysis. The examination revealed that the knockout induction caused a significantly decreased number of mature astrocytes at an early developmental timepoint compared to control animals. Additionally, the delayed maturation of astrocytes also caused a reduced activity of neurons within the hippocampus. As previous studies showed that the glial specification and maturation of astrocytes is dependent on the signaling cascades Ras/Raf/MEK/Erk and PI3K/Akt, the phosphorylation of the signaling molecules Erk1/2 and Akt was analyzed. The hippocampal tissue of LRP1-deficient animals at P21 showed a significantly decreased amount of activated Erk in comparison to control tissue leading to the conclusion that the activation of this signaling cascade is dependent on LRP1 in astrocytes, which in turn is necessary for proper maturation of astrocytes. Our results showed that the deletion of LRP1 at an early developmental timepoint caused a delayed maturation of astrocytes in the hippocampus based on an altered activation of the Ras/Raf/MEK/Erk signaling pathway. However, with ongoing development these effects were compensated and the number of mature astrocytes was comparable as well as the activity of neurons. Therefore, LRP1 acts as an early regulator of the differentiation and maturation of astrocytes within the hippocampus. Frontiers Media S.A. 2021-02-18 /pmc/articles/PMC7930235/ /pubmed/33679332 http://dx.doi.org/10.3389/fncel.2021.642521 Text en Copyright © 2021 Romeo, Boden-El Mourabit, Scheller, Mark and Faissner. http://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
Romeo, Ramona
Boden-El Mourabit, Damian
Scheller, Anja
Mark, Melanie D.
Faissner, Andreas
Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
title Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
title_full Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
title_fullStr Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
title_full_unstemmed Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
title_short Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation
title_sort low-density lipoprotein receptor-related protein 1 (lrp1) as a novel regulator of early astroglial differentiation
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930235/
https://www.ncbi.nlm.nih.gov/pubmed/33679332
http://dx.doi.org/10.3389/fncel.2021.642521
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