The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood-brain barrier formation and maturation
- The Rockefeller University, United States
- Howard Hughes Medical Institute, United States
- University of Munich, Germany
- Tianjin Medical University Cancer Institute and Hospital, China
Abstract
The blood-brain barrier (BBB) of Drosophila is comprised of a thin epithelial layer of subperineural glia (SPG), which ensheath the nerve cord and insulate it against the potassium-rich hemolymph by forming intercellular septate junctions (SJs). Previously, we identified a novel Gi/Go protein-coupled receptor (GPCR), Moody, as a key factor in BBB formation at the embryonic stage. However, the molecular and cellular mechanisms of Moody signaling in BBB formation and maturation remain unclear. Here, we identify cAMP-dependent protein kinase A (PKA) as a crucial antagonistic Moody effector that is required for the formation, as well as for the continued SPG growth and BBB maintenance in the larva and adult stage. We show that PKA is enriched at the basal side of the SPG cell and that this polarized activity of the Moody/PKA pathway finely tunes the enormous cell growth and BBB integrity. Moody/PKA signaling precisely regulates the actomyosin contractility, vesicle trafficking, and the proper SJ organization in a highly coordinated spatiotemporal manner. These effects are mediated in part by PKA's molecular targets MLCK and Rho1. Moreover, 3D reconstruction of SJ ultrastructure demonstrates that the continuity of individual SJ segments, and not their total length, is crucial for generating a proper paracellular seal. Based on these findings, we propose that polarized Moody/PKA signaling plays a central role in controlling the cell growth and maintaining BBB integrity during the continuous morphogenesis of the SPG secondary epithelium, which is critical to maintain tissue size and brain homeostasis during organogenesis.
Data availability
All data generated or analysed during this study are included in Dyrad generic databases with DOI https://doi.org/10.5061/dryad.fj6q573tx.Source data files have been provided for Figures 1, 2, 3, 4, 6 and Figure supplement 2 and 5.
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The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood-brain barrier formation and maturationhttps://creativecommons.org/publicdomain/zero/1.0/.
Article and author information
Author details
Funding
National Institutes of Health (5R01EY011560)
- Xiaoling Li
- Ulrike Gaul
Deutsche Forschungsgemeinschaft (SFB 646,SFB1064)
- Ulrike Gaul
Bundesministerium für Bildung und Forschung (Alexander von Humboldt-Professorship)
- Ulrike Gaul
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Chris Q Doe, Howard Hughes Medical Institute, University of Oregon, United States
Version history
- Received: March 10, 2021
- Preprint posted: March 11, 2021 (view preprint)
- Accepted: August 11, 2021
- Accepted Manuscript published: August 12, 2021 (version 1)
- Version of Record published: August 26, 2021 (version 2)
Copyright
© 2021, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood-brain barrier formation and maturation
eLife 10:e68275.
https://doi.org/10.7554/eLife.68275
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