The purinergic receptor P2Y 13 controls the activation and mode of division of adult ventricular–subventricular zone neural stem cells

ABSTRACT The subependymal zone (SEZ) of the mammalian brain is the most active germinal area that continues to generate newborn neurons throughout life. This area harbors a population of neural stem cells (NSCs) that can be found in different states of activation, each differing in proliferative capacity and molecular signature: quiescent NSCs (qNSCs), primed NSCs (pNSCs), and activated NSCs (aNSCs). There is currently a void in terms of the specific markers available to effectively discern between these transient states. Likewise, the molecular signaling mechanisms controlling the transition from quiescence to activation remain largely unexplored, as do the factors influencing the decision between differentiation and self-renewal during NSC division. Here, we present evidence that the metabotropic P2Y 13 purinergic receptor plays a critical role in regulating adult neurogenesis. We found that P2Y 13 is specifically expressed in NSCs within the adult SEZ and that its levels can be used to distinguish qNSCs from aNSCs. Functionally, P2Y 13 signaling promotes NSC activation, enhancing lineage progression, while dampening their self-renewal capacity. Conversely, pharmacological blockade or genetic silencing of the P2Y 13 receptor favors NSC quiescence. Thus, we identified the metabotropic P2Y 13 purinergic receptor as a pivotal modulator of NSC dynamics, influencing both the balance between NSC quiescence and activation and the mode of NSC division at the subependymal zone.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-11-04
DOI
https://doi.org/10.1073/pnas.2618940123
Primary Topic
Neurogenesis and neuroplasticity mechanisms
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article
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article

The purinergic receptor P2Y 13 controls the activation and mode of division of adult ventricular–subventricular zone neural stem cells

Raquel Pérez‐Sen, Marina Arribas-Blázquez, Paloma Bragado, Antonio R. Artalejo et al.
Proceedings of the National Academy of Sciences
Neurogenesis and neuroplasticity mechanisms
article

The purinergic receptor P2Y 13 controls the activation and mode of division of adult ventricular–subventricular zone neural stem cells

Raquel Pérez‐Sen, Marina Arribas-Blázquez, Paloma Bragado, Antonio R. Artalejo, Armando Reyes‐Palomares, Celia Llorente-Sáez, Benedikt Berninger, Julia Serrano-López, Ana Domingo-Muelas, David de Agustín-Durán, Lucía Paniagua‐Herranz, Pere Duart-Abadía, Lucia Gallego, Esmerilda G. Delicado, Marina Leonor Pérez-Sanz, Luis Alcides Olivos-Oré, Isabel Fariñas, Sergio Gascón, Rosa Gómez‐Villafuertes, Álvaro Gutiérrez-Uzquiza, África Vincelle-Nieto, Araceli Garcia-Mora, Diana Manzano-Franco, Felipe Ortega
article en

Abstract

ABSTRACT The subependymal zone (SEZ) of the mammalian brain is the most active germinal area that continues to generate newborn neurons throughout life. This area harbors a population of neural stem cells (NSCs) that can be found in different states of activation, each differing in proliferative capacity and molecular signature: quiescent NSCs (qNSCs), primed NSCs (pNSCs), and activated NSCs (aNSCs). There is currently a void in terms of the specific markers available to effectively discern between these transient states. Likewise, the molecular signaling mechanisms controlling the transition from quiescence to activation remain largely unexplored, as do the factors influencing the decision between differentiation and self-renewal during NSC division. Here, we present evidence that the metabotropic P2Y 13 purinergic receptor plays a critical role in regulating adult neurogenesis. We found that P2Y 13 is specifically expressed in NSCs within the adult SEZ and that its levels can be used to distinguish qNSCs from aNSCs. Functionally, P2Y 13 signaling promotes NSC activation, enhancing lineage progression, while dampening their self-renewal capacity. Conversely, pharmacological blockade or genetic silencing of the P2Y 13 receptor favors NSC quiescence. Thus, we identified the metabotropic P2Y 13 purinergic receptor as a pivotal modulator of NSC dynamics, influencing both the balance between NSC quiescence and activation and the mode of NSC division at the subependymal zone.

Proceedings of the National Academy of SciencesVol. 123(45)
Universidad Complutense de Madrid (ES), Consejo Superior de Investigaciones Científicas (ES), Universitat de València (ES), King's College London (GB), Johannes Gutenberg University Mainz (DE), Instituto Cajal (ES), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), University Medical Center of the Johannes Gutenberg University Mainz (DE), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES), Instituto de Biomedicina y Biotecnología de Cantabria (ES), Centro de Investigación Biomédica en Red (ES), Instituto de Biología Molecular y Celular de Plantas (ES), MRC Centre for Neurodevelopmental Disorders (GB), Universidad de Málaga (ES), Medical Research Council (GB)
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