PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling
Brain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) are important signaling proteins that regulate dendritic growth and maintenance in the central nervous system (CNS). After binding of BDNF, TrkB is endocytosed into endosomes and continues signaling within the cell...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1009404/full |
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| author | Guillermo Moya-Alvarado Xavier Valero-Peña Alejandro Aguirre-Soto Fernando J. Bustos Oscar M. Lazo Francisca C. Bronfman |
| author_facet | Guillermo Moya-Alvarado Xavier Valero-Peña Alejandro Aguirre-Soto Fernando J. Bustos Oscar M. Lazo Francisca C. Bronfman |
| author_sort | Guillermo Moya-Alvarado |
| collection | DOAJ |
| description | Brain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) are important signaling proteins that regulate dendritic growth and maintenance in the central nervous system (CNS). After binding of BDNF, TrkB is endocytosed into endosomes and continues signaling within the cell soma, dendrites, and axon. In previous studies, we showed that BDNF signaling initiated in axons triggers long-distance signaling, inducing dendritic arborization in a CREB-dependent manner in cell bodies, processes that depend on axonal dynein and TrkB activities. The binding of BDNF to TrkB triggers the activation of different signaling pathways, including the ERK, PLC-γ and PI3K-mTOR pathways, to induce dendritic growth and synaptic plasticity. How TrkB downstream pathways regulate long-distance signaling is unclear. Here, we studied the role of PLC-γ-Ca2+ in BDNF-induced long-distance signaling using compartmentalized microfluidic cultures. We found that dendritic branching and CREB phosphorylation induced by axonal BDNF stimulation require the activation of PLC-γ in the axons of cortical neurons. Locally, in axons, BDNF increases PLC-γ phosphorylation and induces intracellular Ca2+ waves in a PLC-γ-dependent manner. In parallel, we observed that BDNF-containing signaling endosomes transport to the cell body was dependent on PLC-γ activity and intracellular Ca2+ stores. Furthermore, the activity of PLC-γ is required for BDNF-dependent TrkB endocytosis, suggesting a role for the TrkB/PLC-γ signaling pathway in axonal signaling endosome formation. |
| first_indexed | 2024-04-24T11:36:45Z |
| format | Article |
| id | doaj.art-e38137c622b04ea38e1bba9c58359de0 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-24T11:36:45Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-e38137c622b04ea38e1bba9c58359de02024-04-10T05:20:51ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-04-011710.3389/fnmol.2024.10094041009404PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signalingGuillermo Moya-Alvarado0Xavier Valero-Peña1Alejandro Aguirre-Soto2Fernando J. Bustos3Oscar M. Lazo4Francisca C. Bronfman5Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile (UC), Santiago, ChileNeuroSignaling Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, ChileNeuroSignaling Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, ChileConstantin-Paton Research Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, ChileDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United KingdomNeuroSignaling Laboratory, Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, ChileBrain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) are important signaling proteins that regulate dendritic growth and maintenance in the central nervous system (CNS). After binding of BDNF, TrkB is endocytosed into endosomes and continues signaling within the cell soma, dendrites, and axon. In previous studies, we showed that BDNF signaling initiated in axons triggers long-distance signaling, inducing dendritic arborization in a CREB-dependent manner in cell bodies, processes that depend on axonal dynein and TrkB activities. The binding of BDNF to TrkB triggers the activation of different signaling pathways, including the ERK, PLC-γ and PI3K-mTOR pathways, to induce dendritic growth and synaptic plasticity. How TrkB downstream pathways regulate long-distance signaling is unclear. Here, we studied the role of PLC-γ-Ca2+ in BDNF-induced long-distance signaling using compartmentalized microfluidic cultures. We found that dendritic branching and CREB phosphorylation induced by axonal BDNF stimulation require the activation of PLC-γ in the axons of cortical neurons. Locally, in axons, BDNF increases PLC-γ phosphorylation and induces intracellular Ca2+ waves in a PLC-γ-dependent manner. In parallel, we observed that BDNF-containing signaling endosomes transport to the cell body was dependent on PLC-γ activity and intracellular Ca2+ stores. Furthermore, the activity of PLC-γ is required for BDNF-dependent TrkB endocytosis, suggesting a role for the TrkB/PLC-γ signaling pathway in axonal signaling endosome formation.https://www.frontiersin.org/articles/10.3389/fnmol.2024.1009404/fullPLC-γbrain-derived neurotrophic factorTrkBaxonal transportsignaling endosomesdendritic branching |
| spellingShingle | Guillermo Moya-Alvarado Xavier Valero-Peña Alejandro Aguirre-Soto Fernando J. Bustos Oscar M. Lazo Francisca C. Bronfman PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling Frontiers in Molecular Neuroscience PLC-γ brain-derived neurotrophic factor TrkB axonal transport signaling endosomes dendritic branching |
| title | PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling |
| title_full | PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling |
| title_fullStr | PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling |
| title_full_unstemmed | PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling |
| title_short | PLC-γ-Ca2+ pathway regulates axonal TrkB endocytosis and is required for long-distance propagation of BDNF signaling |
| title_sort | plc γ ca2 pathway regulates axonal trkb endocytosis and is required for long distance propagation of bdnf signaling |
| topic | PLC-γ brain-derived neurotrophic factor TrkB axonal transport signaling endosomes dendritic branching |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1009404/full |
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