Abstract
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.
Highlights
Astrocytes are the most abundant cell type within the central nervous system (CNS) and were formerly known as passive players supplying neurons with energy substrates and providing structural support (Yong et al, 1998; Gordon et al, 2007; Iadecola and Nedergaard, 2007; Sofroniew and Vinters, 2010)
We investigated the influence of lipoprotein receptor-related protein 1 (LRP1) on astrocytes in vitro, where we observed that the knockout of LRP1 in primary cortical astrocytes caused an altered expression of mature astrocytic markers
We have previously shown that the deletion of Lrp1 in neural stem and precursor cells leads to an increased number in GFAPpositive astrocytes (Safina et al, 2016) and that the absence of Lrp1 in astrocytes caused a delayed maturation and an altered neuronal transmission in neurons in vitro (Romeo et al, 2021)
Summary
Astrocytes are the most abundant cell type within the central nervous system (CNS) and were formerly known as passive players supplying neurons with energy substrates and providing structural support (Yong et al, 1998; Gordon et al, 2007; Iadecola and Nedergaard, 2007; Sofroniew and Vinters, 2010). Previous studies have shown that the glial specification is influenced by the activation of the Ras/Raf/MEK/Erk pathway (Franzdóttir et al, 2009; Li et al, 2012). The activity of these signaling pathways is regulated by the formation of cell surface receptor complexes causing intracellular signaling cascades. One known activator of the Ras/Raf/MEK/Erk pathway is the complex formation between the low-density lipoprotein receptor-related protein 1 (LRP1) with the plateletderived growth factor receptor β (PDGFRβ) (Boucher et al, 2002; Loukinova et al, 2002) or tropomyosin receptor kinase A (trkA) (Spuch et al, 2012). The association of LRP1 with PDGFRβ influences the activation of the PI3K/Akt pathway, another important signaling cascade involved in glia specification (Muratoglu et al, 2010)
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