RT Journal Article
T1 P2X purinergic receptors are required for correct cortical development in human brain organoids
A1 Benito León, María
A1 Serrano-López, Julia
A1 Llorente-Sáez, Celia
A1 Arribas Blázquez, Marina
A1 Olivos Ore, Luis Alcides
A1 Pravata, Veronica
A1 Pérez Sen, Raquel
A1 García Delicado, Esmerilda
A1 Drukker, Micha
A1 Rodríguez Artalejo, Antonio
A1 Cappello, Silvia
A1 Gómez Villafuertes, María Rosa
A1 Ortega De La O, Felipe
AB The human neocortex represents a crucial evolutionary advance, the formation of which requires the tight and precise orchestration of both intracellular and extracellular signals. Structures grown in three-dimensional cultures, specifically human-induced pluripotent stem cells (hIPSCs)-derived cerebral organoids (COs), have been fundamental to study the signals that regulate the formation of the cortex, overcoming the limitations of 2D cultures. Amongst these, purinergic signaling driven by extracellular ATP and other nucleotides may encode crucial intercellular communications that govern central nervous system (CNS) development. The ATP that accumulates in the extracellular milieu can interact with both ionotropic P2X and metabotropic P2Y receptors on cells to exert its modulating effects. Although widely studied in different animal models, little is known about the expression and function of this signaling system in the human cortex. Thus, here we analyzed the expression of P2X receptor subunits comprehensively throughout the entire process of CO development, confirming that P2X receptors are functional in ventricular structures of the human cortex. Specifically, we detected the expression of P2X1, P2X4, and P2X6 in CO, showing distinct distributions in Nestin+ radial glial cells and/or DCX+ newborn neurons. Significantly, we also show how prolonged pharmacological inhibition of P2X activity affects CO development, resulting in smaller organoids with fewer and less well-organized cortical ventricles. Altogether, our findings point to a relevant role of purinergic signaling during the formation of the human cerebral cortex.
PB Elsevier
SN 0028-3908
YR 2026
FD 2026
LK https://hdl.handle.net/20.500.14352/128602
UL https://hdl.handle.net/20.500.14352/128602
LA eng
NO Benito-León, M., Serrano-López, J., Llorente-Sáez, C., Arribas-Blázquez, M., Olivos-Oré, L. A., Pravata, V., Pérez-Sen, R., Delicado, E. G., Drukker, M., Artalejo, A. R., Cappello, S., Gómez-Villafuertes, R., & Ortega, F. (2025). P2X purinergic receptors are required for correct cortical development in human brain organoids. Neuropharmacology, 284, 110784. Advance online publication. https://doi.org/10.1016/j.neuropharm.2025.110784
NO Credit authorship contribution statement María Benito-Leon: ´ Methodology, Formal analysis, Data curation. Julia Serrano-Lopez: ´ Methodology, Formal analysis, Data curation. Celia Llorente-Saez: ´ Methodology, Formal analysis, Data curation. Marina Arribas-Blazquez: ´ Writing – original draft, Methodology, Formal analysis, Data curation. Luis A. Olivos-Ore: ´ Writing – original draft, Methodology, Formal analysis, Data curation. Veronica Pravata: Formal analysis, Data curation. Raquel Perez-Sen: ´ Writing – original draft, Validation, Methodology, Formal analysis, Data curation. Esmerilda G. Delicado: Writing – original draft, Visualization, Vali dation, Formal analysis, Data curation. Micha Drukker: Visualization, Validation, Resources, Methodology. Antonio R. Artalejo: Writing – original draft, Visualization, Validation, Methodology, Formal analysis, Data curation. Silvia Cappello: Visualization, Validation, Resources, Methodology, Formal analysis, Data curation. Rosa Gomez-Villa ´  fuertes: Writing – original draft, Supervision, Methodology, Formal analysis, Data curation, Conceptualization. Felipe Ortega: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.
NO Ministerio de Ciencia, Innovacion y Universidades (España)
NO Red de Excelencia Consolider-Ingenio Spanish Ion Channel Initiative
NO Fundación Ramón Areces
NO European Commission
NO Comunidad de Madrid
NO Universidad Complutense de Madrid
NO Banco de Santander
DS Docta Complutense
RD 30 dic 2025