E-Mail: lleyton@med.uchile.cl
Dr. Lisette Leyton is a Biochemist from the Faculty of Chemical and Pharmaceutical Sciences, University of Chile. Dr. Leyton obtained her PhD in Sciences in the Faculty of Sciences, University of Chile. She is currently a Professor of the Faculty of Medicine, University of Chile and also the Coordinator of the Committee of the Joint Degree Doctoral Program in Biomedical Sciences of the same Faculty.
Signal transduction pathways triggered by cell-cell and cell-matrix interactions. Rho GTPases involved in cell adhesion and migration. Our model includes neuron-astrocyte interaction, its function in astrocyte activation (morphological changes, adhesion and migration) and neuronal cell death under pro-inflammatory stimuli.
Astrocytes are ubiquitously present throughout the brain and intimately associated with neurons. Upon injury or in response to inflammation, astrocytes become reactive, migrate, increase size and participate in the formation of the glial scar. In doing so, the glial scar generates a non-permissive environment for neuronal regeneration. Molecular mechanisms responsible for the lack of neuronal regeneration in the adult CNS are still unclear, possibly due to the participation of multiple inhibitory cell-cell, as well as cell-matrix interactions. We have shown that Thy-1/CD90 clusters αvβ3 integrin in astrocytes (Lagos-Cabré et al., 2018) to induce tyrosine phosphorylation of focal adhesion proteins (Leyton et al., 2001), RhoA activation (Ávalos et al., 2002, 2004) and the formation of focal adhesions and stress fibers. Focal adhesions anchor stress fibers to the plasma membrane, and are implicated in cell migration, growth and differentiation. Using the Surface Plasmon Resonance technique, the interaction between Thy-1/CD90 and αvβ3 integrin was shown to be direct (Hermosilla et al., 2008). Additionally, Thy-1/CD90-induced integrin signals require an additional interaction with the proteoglycan Syndecan-4, as evidenced by silencing Syndecan-4 expression (Avalos et al., 2009). Furthermore, Thy-1/CD90 requires both αvβ3 integrin and Syndecan-4 engagement to stimulate astrocytes via PKCα and RhoA-dependent pathways (Ávalos, et al., 2009). Finally, since PKCα activation is calcium-dependent, we studied the origin of calcium elevation. We documented that αvβ3 integrin engagement in astrocytes by Thy-1/CD90, triggers ATP release though Connexin43 and Pannexin1 hemichannels, that increased levels of ATP activates P2X7 pore-forming channels, and permits calcium entry, increasing intracellular calcium levels. All these events are required for adhesion and migration of astrocytes (Henríquez, et al., 2011; Alvarez et a., 2016). These signaling events are temporally regulated, and the prolonged stimulation with Thy-1/CD90 leads to disassembly-assembly of focal adhesions in a dynamic process that induces astrocyte migration in a PI3K and Rac1-dependent manner (Kong, et al., 2013). Importantly, only reactive astrocytes respond to Thy-1/CD90 and this effect is associated with increased levels of αvβ3 integrin under inflammatory conditions. In addition, overexpression of β3 integrin is sufficient to induce a reactive phenotype and to respond to Thy-1/CD90 suggesting that by controlling β3 Integrin levels, it is possible to modulate astrocyte reactivity (Lagos-Cabré et al., 2017)
From: Lagos-Cabré R, Burgos-Bravo F, Avalos AM and Leyton L (2020). Connexins in Astrocyte Migration. Front. Pharmacol. 10:1546. doi: 10.3389/fphar.2019.01546
On the other hand, αVβ3 integrin acts as a ligand for Thy-1/CD90, and upon binding, the interaction not only restricts the growth of neurites, but also induces retraction of already existing processes by inducing Thy-1/CD90 clustering and recruitment of Src (Herrera-Molina, et al., 2012). Thy-1/CD90 clusters in a complex with CBP and Csk inhibiting Src activity, and additionally modulating downstream pathways, including the p190RhoGAP/RhoA/ROCK axis, MLCII, and cofilin, which promotes neurite contraction (Maldonado et al., 2017).
From: Leyton L, Díaz J, Martínez S, Palacios E, Pérez LA and Pérez RD (2019) Thy-1/CD90 a Bidirectional and Lateral Signaling Scaffold. Front. Cell Dev. Biol. 7:132. doi: 10.3389/fcell.2019.00132
These observations argue that Thy-1/CD90 functions in a bimodal fashion, as a receptor on neuronal cells and as a ligand for αVβ3 integrin on astrocytes. Understanding such mechanisms should yield insights to astrogliosis, a process triggered in astrocytes following brain injury that precludes neuronal regeneration. These studies are expected to yield a better understanding of molecular mechanisms controlling neurite outgrowth and astrocyte function.
