Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase
Abstract Wnt signaling plays a key role in neurodevelopment and neuronal maturation. Specifically, Wnt5a stimulates postsynaptic assemblies, increases glutamatergic neurotransmission and, through calcium signaling, generates nitric oxide (NO). Trying to unveil the molecular pathway triggering these...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-86708-y |
| _version_ | 1818428881120526336 |
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| author | Eva Ramos-Fernández Macarena S. Arrázola Carolina A. Oliva Sebastián B. Arredondo Lorena Varela-Nallar Nibaldo C. Inestrosa |
| author_facet | Eva Ramos-Fernández Macarena S. Arrázola Carolina A. Oliva Sebastián B. Arredondo Lorena Varela-Nallar Nibaldo C. Inestrosa |
| author_sort | Eva Ramos-Fernández |
| collection | DOAJ |
| description | Abstract Wnt signaling plays a key role in neurodevelopment and neuronal maturation. Specifically, Wnt5a stimulates postsynaptic assemblies, increases glutamatergic neurotransmission and, through calcium signaling, generates nitric oxide (NO). Trying to unveil the molecular pathway triggering these postsynaptic effects, we found that Wnt5a treatment induces a time-dependent increases in the length of the postsynaptic density (PSD), elicits novel synaptic contacts and facilitates F-actin flow both in in vitro and ex vivo models. These effects were partially abolished by the inhibition of the Heme-regulated eukaryotic initiation factor 2α (HRI) kinase, a kinase which phosphorylates the initiation translational factor eIF2α. When phosphorylated, eIF2α normally avoids the translation of proteins not needed during stress conditions, in order to avoid unnecessary energetic expenses. However, phosphorylated eIF2α promotes the translation of some proteins with more than one open reading frame in its 5′ untranslated region. One of these proteins targeted by Wnt-HRI-eIF2α mediated translation is the GluN2B subunit of the NMDA receptor. The identified increase in GluN2B expression correlated with increased NMDA receptor function. Considering that NMDA receptors are crucial for excitatory synaptic transmission, the molecular pathway described here contributes to the understanding of the fast and plastic translational mechanisms activated during learning and memory processes. |
| first_indexed | 2024-12-14T15:08:40Z |
| format | Article |
| id | doaj.art-390ac201791347b586eeab76239c7001 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:08:40Z |
| publishDate | 2021-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-390ac201791347b586eeab76239c70012022-12-21T22:56:37ZengNature PortfolioScientific Reports2045-23222021-04-0111112010.1038/s41598-021-86708-yWnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinaseEva Ramos-Fernández0Macarena S. Arrázola1Carolina A. Oliva2Sebastián B. Arredondo3Lorena Varela-Nallar4Nibaldo C. Inestrosa5Centro de Envejecimiento y Regeneración (CARE UC), CARE UC Biomedical Center, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileCentro de Envejecimiento y Regeneración (CARE UC), CARE UC Biomedical Center, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileCentro de Envejecimiento y Regeneración (CARE UC), CARE UC Biomedical Center, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileInstituto de Ciencias Biomédicas, Facultad de Medicina y Facultad de Ciencias de La Vida, Universidad Andrés BelloInstituto de Ciencias Biomédicas, Facultad de Medicina y Facultad de Ciencias de La Vida, Universidad Andrés BelloCentro de Envejecimiento y Regeneración (CARE UC), CARE UC Biomedical Center, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileAbstract Wnt signaling plays a key role in neurodevelopment and neuronal maturation. Specifically, Wnt5a stimulates postsynaptic assemblies, increases glutamatergic neurotransmission and, through calcium signaling, generates nitric oxide (NO). Trying to unveil the molecular pathway triggering these postsynaptic effects, we found that Wnt5a treatment induces a time-dependent increases in the length of the postsynaptic density (PSD), elicits novel synaptic contacts and facilitates F-actin flow both in in vitro and ex vivo models. These effects were partially abolished by the inhibition of the Heme-regulated eukaryotic initiation factor 2α (HRI) kinase, a kinase which phosphorylates the initiation translational factor eIF2α. When phosphorylated, eIF2α normally avoids the translation of proteins not needed during stress conditions, in order to avoid unnecessary energetic expenses. However, phosphorylated eIF2α promotes the translation of some proteins with more than one open reading frame in its 5′ untranslated region. One of these proteins targeted by Wnt-HRI-eIF2α mediated translation is the GluN2B subunit of the NMDA receptor. The identified increase in GluN2B expression correlated with increased NMDA receptor function. Considering that NMDA receptors are crucial for excitatory synaptic transmission, the molecular pathway described here contributes to the understanding of the fast and plastic translational mechanisms activated during learning and memory processes.https://doi.org/10.1038/s41598-021-86708-y |
| spellingShingle | Eva Ramos-Fernández Macarena S. Arrázola Carolina A. Oliva Sebastián B. Arredondo Lorena Varela-Nallar Nibaldo C. Inestrosa Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase Scientific Reports |
| title | Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase |
| title_full | Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase |
| title_fullStr | Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase |
| title_full_unstemmed | Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase |
| title_short | Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase |
| title_sort | wnt5a promotes hippocampal postsynaptic development and glun2b induced expression via the eif2α hri kinase |
| url | https://doi.org/10.1038/s41598-021-86708-y |
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