Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation
Date
2023
Authors
Freitas-Andrade, Moises
Comin, Cesar H.
Van Dyken, Peter
Ouellette, Julie
Raman-Nair, Joanna
Blakeley, Nicole
Liu, Qing Yan
Leclerc, Sonia
Pan, Youlian
Liu, Ziying
Journal Title
Journal ISSN
Volume Title
Publisher
Nature Communications
Abstract
Astrocytes are intimately linked with brain blood vessels, an essential relationship for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as an important player in postnatal gliovascular maturation.
Description
We thank Drs. Simon Chen and Chenghua Gu for their valuable comments on the manuscript; the histology services provided by the Louise Pelletier Histopathology Core Facility at the University of Ottawa; the animal care and veterinary services at the University of Ottawa; and Jinjing Gong, Katie Barret, Colleen Urban, Elizabeth Mahoney and Seth Meyers (NanoString Technologies, Inc.) for coordinating spatial transcriptomics experiments. We would also like to thank Cédric Gravel for help with immunostaining work.
Keywords
Citation
Freitas-Andrade, M., Comin, C. H., Van Dyken, P., Ouellette, J., Raman-Nair, J., Blakeley, N., ... Lacoste, Baptiste. (2023). Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation. Nature Communications, 14, 4965. https://doi.org/10.1038/s41467-023-40682-3