Astrocytes modulate neuronal development by S100A6 signaling

Valentina Cinquina, Evgenii O. Tretiakov, Predrag Kalaba, Alán Alpár, Daniela Calvigioni, Fabiana Piscitelli, Erik Keimpema, Vincenzo Di Marzo, Alexej Verkhratsky and Tibor Harkany ()
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Valentina Cinquina: Medical University of Vienna
Evgenii O. Tretiakov: Medical University of Vienna
Predrag Kalaba: University of Vienna
Alán Alpár: Semmelweis University
Daniela Calvigioni: Medical University of Vienna
Fabiana Piscitelli: National Research Council (CNR)
Erik Keimpema: Medical University of Vienna
Vincenzo Di Marzo: National Research Council (CNR)
Alexej Verkhratsky: The University of Manchester
Tibor Harkany: Medical University of Vienna

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Neuronal morphogenesis relies on intercellular signaling. Astrocytes release metabolites, trophic, and guidance factors to promote neuronal maturation. In contrast, the mechanisms by which astrocytes could limit and stabilize neuronal connectivity remain less explored. Here, we find cortical astrocytes to express and release S100A6, a Ca2+-binding protein (‘calcyclin’). Simultaneously, the majority of cortical neurons expressed calcyclin-binding protein (CaCyBp), a bona fide binding partner for S100A6. In neurons, CaCyBp maintains the unfolded protein response pathway, thereby controlling proteostasis. When released, S100A6 inhibits CaCyBp-mediated signaling, thus slowing protein turnover, and, consequently, neuritogenesis. In the cerebral cortex of male mice, S100A6-CaCyBp signaling during gestation is sensitive to the mother’s nutritional status, particularly eicosapentaenoic acid intake. Thus, a member of the S100 protein family acts as an astroglia-derived morphogen, whose action on neurons is modulated by environmental factors.

Date: 2025
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DOI: 10.1038/s41467-025-64405-y

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