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Neuronal THY1 Signaling Maintains Astrocytes in a Quiescent State

Juliane Loui,U. Krügel,U. Winkler,Anja Reinert,Dorit John,J. Hirrlinger,Anja Saalbach

Published 2025 in Glia

ABSTRACT

THY1 is a cell surface protein of mature neurons. Although the Thy1 promoter is widely used as a neuron‐specific promoter for transgenic expression, the role of the endogenous THY1 protein in the brain remains largely unknown. As THY1 receptors are expressed on astrocytes, THY1 may mediate signaling between both cell types. We therefore investigated the role of THY1 signaling in neuron‐astrocyte communication using a full as well as a neuron‐specific Thy1‐knockout mouse model. Compared to wild‐type mice, aged individuals of both strains exhibited an increased expression of a subset of astrocyte activation‐associated genes, such as glial fibrillary acidic protein (Gfap), vimentin (Vim), and tenascin C (Tnc), whereas others appeared unaffected. Importantly, a cortical injury caused a permanent astrocytic activation in mice with neuronal Thy1 deletion, reflected by persistent high GFAP expression. The THY1‐associated modulation of gene expression was confirmed in primary astrocytes cultured with or without recombinant THY1. Moreover, functional assays indicate that THY1 inhibits astrocyte proliferation while promoting apoptosis. Interaction of neuronal THY1 with ITGB1 on astrocytes was identified to be responsible for the THY1‐mediated control of astrocyte activation. These data strongly suggest that THY1‐bearing neurons keep astrocytes in a quiescent state. Consequently, a depletion of THY1 supports the development of a partially activated astrocyte phenotype characterized by increased expression of intermediate filaments, increased proliferative capacity, and reduced cell death. Our findings demonstrate that neuronal THY1 is a still unrecognized novel regulator in the communication between astrocytes and neurons involved in the maintenance and restoration of tissue homeostasis in the brain.

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