The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation

The blood–brain barrier (BBB) of Drosophila comprises 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 rece...

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Autores principales:	Xiaoling Li, Richard Fetter, Tina Schwabe, Christophe Jung, Liren Liu, Hermann Steller, Ulrike Gaul
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	blood-brain barrier GPCR signaling PKA apical-basal polarity septate junction epithelium development Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1a4165662da7452f9862cb4dcd70373d
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spelling	oai:doaj.org-article:1a4165662da7452f9862cb4dcd70373d2021-11-25T10:22:54ZThe cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation10.7554/eLife.682752050-084Xe68275https://doaj.org/article/1a4165662da7452f9862cb4dcd70373d2021-08-01T00:00:00Zhttps://elifesciences.org/articles/68275https://doaj.org/toc/2050-084XThe blood–brain barrier (BBB) of Drosophila comprises 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.Xiaoling LiRichard FetterTina SchwabeChristophe JungLiren LiuHermann StellerUlrike GauleLife Sciences Publications Ltdarticleblood-brain barrierGPCR signalingPKAapical-basal polarityseptate junctionepithelium developmentMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	blood-brain barrier GPCR signaling PKA apical-basal polarity septate junction epithelium development Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	blood-brain barrier GPCR signaling PKA apical-basal polarity septate junction epithelium development Medicine R Science Q Biology (General) QH301-705.5 Xiaoling Li Richard Fetter Tina Schwabe Christophe Jung Liren Liu Hermann Steller Ulrike Gaul The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation
description	The blood–brain barrier (BBB) of Drosophila comprises 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.
format	article
author	Xiaoling Li Richard Fetter Tina Schwabe Christophe Jung Liren Liu Hermann Steller Ulrike Gaul
author_facet	Xiaoling Li Richard Fetter Tina Schwabe Christophe Jung Liren Liu Hermann Steller Ulrike Gaul
author_sort	Xiaoling Li
title	The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation
title_short	The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation
title_full	The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation
title_fullStr	The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation
title_full_unstemmed	The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation
title_sort	camp effector pka mediates moody gpcr signaling in drosophila blood–brain barrier formation and maturation
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/1a4165662da7452f9862cb4dcd70373d
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The cAMP effector PKA mediates Moody GPCR signaling in Drosophila blood–brain barrier formation and maturation

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