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Astrocytes modulate neuronal development by S100A6 signaling

This repository contains code and output of the analysis of single-cell RNA sequencing data and experimental results for the article Cinquina V et al., 2024.

Please see file CITATION in the root of your Git repo that contains the citation information.

To see the results of the analysis please visit the analysis website.

Purpose:

We aimed to investigate the role of astrocyte-derived factors in regulating neuronal morphogenesis during brain development. Specifically, we hypothesized that S100A6, a Ca²⁺-binding protein expressed by astrocytes, could act as a gliotransmitter to modulate neuronal development through its interaction with calcyclin-binding protein (CaCyBP) in neurons.

Results:

  1. S100A6 is specifically expressed in astrocytes during late embryonic and early postnatal development of the mouse cortex.
  2. CaCyBP, the binding partner of S100A6, is expressed in neurons during the same developmental period.
  3. S100A6 is released by astrocytes in response to glutamate and eicosapentaenoic acid (EPA) stimulation.
  4. Exogenous S100A6 inhibits neurite outgrowth and reduces CaCyBP levels in neurons.
  5. CaCyBP regulates protein turnover in neurons through the unfolded protein response (UPR) pathway.
  6. Maternal diet, particularly EPA intake, influences S100A6-CaCyBP signaling in the developing fetal brain.

Conclusions:

Our results describe a novel molecular axis of astrocyte-neuron communication, which is unique in limiting neuronal morphogenesis through the ER/UPS pathway. S100A6 acts as an astrocyte-specific gliotransmitter, which regulates neuronal proteostasis through CaCyBP. This signaling pathway is sensitive to environmental factors, particularly maternal nutrition during pregnancy.

Data and Code Availability:

Raw data were obtained from the Single Cell Portal (Tarhan et al., n.d.; Di Bella et al. 2021). All generated data are available in this repository.

The code for the analysis is available at https://github.com/harkany-lab/Cinquina_2024.

References

Di Bella, Daniela J., Ehsan Habibi, Robert R. Stickels, Gabriele Scalia, Juliana Brown, Payman Yadollahpour, Sung Min Yang, et al. 2021. “Molecular logic of cellular diversification in the mouse cerebral cortex.” Nature 595 (7868): 554–59. https://doi.org/10.1038/s41586-021-03670-5.
Tarhan, Leyla, Jon Bistline, Jean Chang, Bryan Galloway, Emily Hanna, and Eric Weitz. n.d. “Single Cell Portal: An Interactive Home for Single-Cell Genomics Data.” https://doi.org/10.1101/2023.07.13.548886.

sessionInfo()
R version 4.4.0 (2024-04-24)
Platform: x86_64-pc-linux-gnu
Running under: Ubuntu 22.04.4 LTS

Matrix products: default
BLAS:   /usr/lib/x86_64-linux-gnu/openblas-pthread/libblas.so.3 
LAPACK: /usr/lib/x86_64-linux-gnu/openblas-pthread/libopenblasp-r0.3.20.so;  LAPACK version 3.10.0

locale:
 [1] LC_CTYPE=en_US.UTF-8       LC_NUMERIC=C              
 [3] LC_TIME=en_US.UTF-8        LC_COLLATE=en_US.UTF-8    
 [5] LC_MONETARY=en_US.UTF-8    LC_MESSAGES=en_US.UTF-8   
 [7] LC_PAPER=en_US.UTF-8       LC_NAME=C                 
 [9] LC_ADDRESS=C               LC_TELEPHONE=C            
[11] LC_MEASUREMENT=en_US.UTF-8 LC_IDENTIFICATION=C       

time zone: Etc/UTC
tzcode source: system (glibc)

attached base packages:
[1] stats     graphics  grDevices utils     datasets  methods   base     

other attached packages:
[1] workflowr_1.7.1

loaded via a namespace (and not attached):
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[17] bslib_0.7.0       pillar_1.9.0      rlang_1.1.4       utf8_1.2.4       
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[25] getPass_0.2-4     fs_1.6.4          sass_0.4.9        cli_3.6.2        
[29] magrittr_2.0.3    ps_1.7.6          digest_0.6.35     processx_3.8.4   
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[37] glue_1.7.0        whisker_0.4.1     fansi_1.0.6       rmarkdown_2.27   
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