Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis
In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of...
| Autores: | , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/712194 |
| Acceso en línea: | http://hdl.handle.net/10486/712194 https://dx.doi.org/10.1038/s41419-023-05995-7 |
| Access Level: | acceso abierto |
| Palabra clave: | Adult adult stem cells animals epidermal growth factor glycogen synthase kinase 3 hippocampus humans mammals mice neural stem cells neurogenesis neurons Biología y Biomedicina / Biología |
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España |
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| dc.title.none.fl_str_mv |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| title |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| spellingShingle |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis del Puerto, Ana Adult adult stem cells animals epidermal growth factor glycogen synthase kinase 3 hippocampus humans mammals mice neural stem cells neurogenesis neurons Biología y Biomedicina / Biología |
| title_short |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| title_full |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| title_fullStr |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| title_full_unstemmed |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| title_sort |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis |
| dc.creator.none.fl_str_mv |
del Puerto, Ana López Fonseca, Coral Simón-García, Ana Martí-Prado, Beatriz Barrios Muñoz, Ana Laura Pose-Utrilla, Julia López-Menéndez, Celia Alcover-Sanchez, Berta Cesca, Fabrizia Schiavo, Giampietro Campanero, Miguel R. Fariñas, Isabel Iglesias, Teresa Porlán Alonso, Eva |
| author |
del Puerto, Ana |
| author_facet |
del Puerto, Ana López Fonseca, Coral Simón-García, Ana Martí-Prado, Beatriz Barrios Muñoz, Ana Laura Pose-Utrilla, Julia López-Menéndez, Celia Alcover-Sanchez, Berta Cesca, Fabrizia Schiavo, Giampietro Campanero, Miguel R. Fariñas, Isabel Iglesias, Teresa Porlán Alonso, Eva |
| author_role |
author |
| author2 |
López Fonseca, Coral Simón-García, Ana Martí-Prado, Beatriz Barrios Muñoz, Ana Laura Pose-Utrilla, Julia López-Menéndez, Celia Alcover-Sanchez, Berta Cesca, Fabrizia Schiavo, Giampietro Campanero, Miguel R. Fariñas, Isabel Iglesias, Teresa Porlán Alonso, Eva |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Departamento de Biología Molecular Facultad de Ciencias |
| dc.subject.none.fl_str_mv |
Adult adult stem cells animals epidermal growth factor glycogen synthase kinase 3 hippocampus humans mammals mice neural stem cells neurogenesis neurons Biología y Biomedicina / Biología |
| topic |
Adult adult stem cells animals epidermal growth factor glycogen synthase kinase 3 hippocampus humans mammals mice neural stem cells neurogenesis neurons Biología y Biomedicina / Biología |
| description |
In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. Current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects accompanied by increased neuroblast death and high loss of newly formed neurons in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. We also show that NSCs with Kidins220 can survive with lower concentrations of EGF than the ones lacking this molecule. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs growth and expansion. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023-08-01 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10486/712194 https://dx.doi.org/10.1038/s41419-023-05995-7 |
| url |
http://hdl.handle.net/10486/712194 https://dx.doi.org/10.1038/s41419-023-05995-7 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Springer Nature |
| publisher.none.fl_str_mv |
Springer Nature |
| dc.source.none.fl_str_mv |
reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid |
| instname_str |
Universidad Autónoma de Madrid |
| reponame_str |
Biblos-e Archivo. Repositorio Institucional de la UAM |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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|
| repository.mail.fl_str_mv |
|
| _version_ |
1869409414768754688 |
| spelling |
Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesisdel Puerto, AnaLópez Fonseca, CoralSimón-García, AnaMartí-Prado, BeatrizBarrios Muñoz, Ana LauraPose-Utrilla, JuliaLópez-Menéndez, CeliaAlcover-Sanchez, BertaCesca, FabriziaSchiavo, GiampietroCampanero, Miguel R.Fariñas, IsabelIglesias, TeresaPorlán Alonso, EvaAdultadult stem cellsanimalsepidermal growth factorglycogen synthase kinase 3hippocampushumansmammalsmiceneural stem cellsneurogenesisneuronsBiología y Biomedicina / BiologíaIn the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. Current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects accompanied by increased neuroblast death and high loss of newly formed neurons in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. We also show that NSCs with Kidins220 can survive with lower concentrations of EGF than the ones lacking this molecule. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs growth and expansion. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepairThis work was funded by grants RYC2014-15991 (MINECO/ESF), SAF2015-67756-R (MCIN/AEI /10.13039/501100011033 and by ERDF “A way of making Europe") and PID2019-104763RB-I00 to EP, PID2020-115218RB-I00 to TI, PID2020-117937GB-I00 to IF, PID2020-115217RB-I00 to MRC, funded by MCIN/AEI/ 10.13039/501100011033; by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED, Instituto de Salud Carlos III, Spain) and collaborative grants CIBERNED-2015-2/06 and 2018/06 to TI and IF; by PROMETEO/2021/028 of Generalitat Valenciana to IF; by Wellcome Senior Investigator Awards (107116/Z/15/Z and 223022/Z/21/Z) and a UK Dementia Research Institute Foundation award (UKDRI 1005) to GS. ADP was supported by grant FJCI-2014-19673 funded by MCIN/AEI/10.13039/501100011033 and by ESF “Investing in your future”; and a CIBERNED contract; AS-G was supported by a contract associated to PID2020-115218RB-I00 project; EP was supported by a Ramón y Cajal contract (RYC2014-15991, MINECO/ESF), ALB-M by grant FPI BES-2016-078481 associated to SAF2015-67756-R to EP. JP-U was supported by a CIBERNED contract. CLF is recipient of a FPI grant funded by UAM. The cost of this publication has been paid in part by “ERDF A way of making Europe” fundsSpringer NatureDepartamento de Biología MolecularFacultad de Ciencias20232023-08-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/712194https://dx.doi.org/10.1038/s41419-023-05995-7reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7121942026-06-23T12:46:27Z |
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15,300719 |