RT Journal Article
T1 Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells
A1 Villarroya‐Beltri, Carolina
A1 Martins, Ana Filipa
A1 García, Alejandro
A1 Giménez, Daniel
A1 Zarzuela, Eduardo
A1 Novo, Mónica
A1 Álamo, Cristina del
A1 González, José
A1 Bonel-Pérez, Gloria
A1 Díaz, Irene
A1 Guillamot, María
A1 Chiesa, Massimo
A1 Losada, Ana
A1 Grana-Castro, Osvaldo
A1 Rovira, Meritxell
A1 Muñoz, Javier
A1 Salazar Roa, María
A1 Malumbres, Marcos
AB Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin‐dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK‐counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline‐directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome‐dependent degradation. Multiomic single‐cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK‐CDC14 axis as a critical molecular switch for linking cell cycle regulation and self‐renewal.
PB EMBO Press
SN 0261-4189
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/97976
UL https://hdl.handle.net/20.500.14352/97976
LA eng
NO Villarroya‐Beltri, Carolina, et al. «Mammalian CDC14 Phosphatases Control Exit from Stemness in Pluripotent Cells». The EMBO Journal, vol. 42, n.o 1, enero de 2023, p. e111251. https://doi.org/10.15252/embj.2022111251.
NO AcknowledgmentsWe thank the Microscopy, Cytometry, Comparative Pathology, Mouse Facility, and Mouse Genome editing core services of the CNIO for their support. We also thank Eva Porlan (UAM, Madrid) for help with neural cultures, and Dr. Mario García‐Domínguez (CABIMER, Seville) for the UTF1 3KR and 5KR mutants. CV received support from the Juan de la Cierva programme, Ministry of Science and Innovation‐Agencia Estatal de Investigación (MCI‐AEI). DG and MSR were supported by the Fundación Científica de la Asociación Española contra el Cáncer (AECC). AFBM and JGM received predoctoral contracts from Foundation La Caixa and the Ministry of Education of Spain (FPI grant BES‐2016‐077901). This work was supported by grants from the European Commission Seventh Framework Programme (ERA‐NET NEURON8‐Full‐815‐094), AEI‐MICIU/FEDER (RTI2018‐095582‐B‐I00 and RED2018‐102723‐T), and the Personalized Medicine and Nanotechnologies in Lung Cancer (iLUNG) and scCANCER programmes from the Comunidad de Madrid (B2017/BMD‐3884 and Y2020/BIO‐6519) to M.M. CNIO is a Severo Ochoa Center of Excellence (AEI‐MICIU CEX2019‐000891‐S).
NO Ministerio de Ciencia e Innovación  (España)
NO Fundación Científica de la Asociación Española contra el Cáncer
NO Fundación La Caixa
NO Comunidad de Madrid
NO European Commission
DS Docta Complutense
RD 11 abr 2025