Astrocytes modulate neuronal development by S100A6 signaling
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 Ca<sup>2+</sup>-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.
Authors
- Vincenzo Di Marzo (ORCID: https://orcid.org/0000-0002-1490-3070)
- Valentina Cinquina (ORCID: https://orcid.org/0000-0002-7365-1395)
- Alán Alpár (ORCID: https://orcid.org/0000-0003-4810-0820)
- Fabiana Piscitelli (ORCID: https://orcid.org/0000-0001-9343-4622)
- Daniela Calvigioni (ORCID: https://orcid.org/0000-0002-6122-9744)
- Tibor Harkany (ORCID: https://orcid.org/0000-0002-6637-5900)
- Erik Keimpema (ORCID: https://orcid.org/0000-0002-7555-6762)
- Alexei Verkhratsky (ORCID: https://orcid.org/0000-0003-2592-9898)
- Predrag Kalaba (ORCID: https://orcid.org/0000-0003-0480-2337)
- Evgenii O. Tretiakov
Institutions
- Semmelweis University (HU)
- Ikerbasque (ES)
- University of Vienna (AT)
- Karolinska Institutet (SE)
- University of Manchester (GB)
- Institut universitaire de cardiologie et de pneumologie de Québec (CA)
- National Research Council (IT)
- Université Laval (CA)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-13
- DOI
- https://doi.org/10.1038/s41467-025-64405-y
- Citations
- 1
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Wellcome Trust
- University of St Andrews
- Institut National de la Santé et de la Recherche Médicale
- Austrian Science Fund
- Universität Wien
- Hjärnfonden
- Karolinska Institutet
- Novo Nordisk
- Vetenskapsrådet
- Medizinische Universität Wien
- Novo Nordisk Fonden