Astrocytes modulate neuronal development by S100A6 signaling

Neuronal morphogenesis relies on intercellular signaling. Astrocytes release metabolites, trophic, and guidance factors to promote neuronal differentiation. In contrast, the mechanisms by which astrocytes could limit and stabilize neuronal connectivity remain less explored. Here, we show cortical astrocytes to express and release S100A6, a Ca2+-binding protein ("calcyclin"). Simultaneously, the majority of cortical neurons express a bona fide binding partner for S100A6, calcyclin-binding protein (CaCyBp). In neurons, CaCyBp maintains unfolded protein response, thereby controlling proteostasis. When released, S100A6 inhibits CaCyBp signaling, thus slowing protein turnover, and inhibiting neuritogenesis. S100A6-CaCyBp signaling during gestation and lactation 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. ### Competing Interest Statement The authors have declared no competing interest.