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Astrocytes modulate neuronal development by S100A6 signaling.

Valentina Cinquina1, Evgenii O Tretiakov1, Predrag Kalaba2

  • 1Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

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|October 13, 2025
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Cortical astrocytes release S100A6, a protein that inhibits neuronal connectivity by binding to CaCyBp. Maternal nutrition, like eicosapentaenoic acid intake, influences this S100A6-CaCyBp signaling during development.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • Neuronal morphogenesis is guided by intercellular signals from astrocytes.
  • Astrocytes provide factors promoting neuronal maturation.
  • Mechanisms by which astrocytes limit and stabilize neuronal connectivity are less understood.

Purpose of the Study:

  • To investigate the role of astrocyte-derived factors in limiting and stabilizing neuronal connectivity.
  • To identify novel signaling pathways involved in astroglia-neuron interactions during development.

Main Methods:

  • Identified S100A6 expression in cortical astrocytes and its binding partner CaCyBp in cortical neurons.
  • Investigated the functional impact of S100A6 on CaCyBp-mediated signaling and proteostasis in neurons.
  • Examined the influence of maternal nutritional status, specifically eicosapentaenoic acid intake, on S100A6-CaCyBp signaling in the developing brain.

Main Results:

  • Cortical astrocytes express and release S100A6, a calcium-binding protein.
  • Cortical neurons express calcyclin-binding protein (CaCyBp), which maintains the unfolded protein response and proteostasis.
  • Released S100A6 inhibits CaCyBp signaling, slowing protein turnover and neuritogenesis.
  • S100A6-CaCyBp signaling in male mice is sensitive to maternal eicosapentaenoic acid intake during gestation.

Conclusions:

  • S100A6 acts as an astroglia-derived morphogen regulating neuronal connectivity.
  • The S100A6-CaCyBp pathway modulates neuritogenesis and proteostasis.
  • Environmental factors, such as maternal nutrition, significantly influence this developmental signaling pathway.