The Wnt-dependent master regulator NKX1-2 controls mouse pre-implantation development

Nakagawa, Shoma; Carnevali, Davide; Tan, Xiangtian; Alvarez, Mariano J.; Parfitt, David-Emlyn; Di Vicino, Umberto; Arumugam, Karthik; Shin, William; Aranda, Sergi; Normanno, Davide; Sebastián Pérez, Rubén; Cannatá, Chiara; Cortes, Paola; Neguembor, Maria Victoria; Shen, Michael M.; Califano, Andrea; Cosma, Maria Pia

The Wnt-dependent master regulator NKX1-2 controls mouse pre-implantation development

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dc.contributor.author Nakagawa, Shoma
dc.contributor.author Carnevali, Davide
dc.contributor.author Tan, Xiangtian
dc.contributor.author Alvarez, Mariano J.
dc.contributor.author Parfitt, David-Emlyn
dc.contributor.author Di Vicino, Umberto
dc.contributor.author Arumugam, Karthik
dc.contributor.author Shin, William
dc.contributor.author Aranda, Sergi
dc.contributor.author Normanno, Davide
dc.contributor.author Sebastián Pérez, Rubén
dc.contributor.author Cannatá, Chiara
dc.contributor.author Cortes, Paola
dc.contributor.author Neguembor, Maria Victoria
dc.contributor.author Shen, Michael M.
dc.contributor.author Califano, Andrea
dc.contributor.author Cosma, Maria Pia
dc.date.accessioned 2024-09-06T06:14:27Z
dc.date.available 2024-09-06T06:14:27Z
dc.date.issued 2024
dc.description.abstract Embryo size, specification, and homeostasis are regulated by a complex gene regulatory and signaling network. Here we used gene expression signatures of Wnt-activated mouse embryonic stem cell (mESC) clones to reverse engineer an mESC regulatory network. We identify NKX1-2 as a novel master regulator of preimplantation embryo development. We find that Nkx1-2 inhibition reduces nascent RNA synthesis, downregulates genes controlling ribosome biogenesis, RNA translation, and transport, and induces severe alteration of nucleolus structure, resulting in the exclusion of RNA polymerase I from nucleoli. In turn, NKX1-2 loss of function leads to chromosome missegregation in the 2- to 4-cell embryo stages, severe decrease in blastomere numbers, alterations of tight junctions (TJs), and impairment of microlumen coarsening. Overall, these changes impair the blastocoel expansion-collapse cycle and embryo cavitation, leading to altered lineage specification and developmental arrest.
dc.description.sponsorship This work was supported by the Ministerio de Ciencia e Innovación, (BFU2017-86760-P (AEI/FEDER, UE) and PID2020-114080GB-100/AEI/10.13039/501100011033 to M.P.C.), the AGAUR grant from Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya, (2017 SGR 689 and 2021-SGR2021-01300 to M.P.C.), the Fundacio La Marato de TV3, (202027-10 to M.P.C.), the NSFC (32270577 to M.P.C.), the European Union’s Horizon 2020 research and innovation program under grant agreement Nº964342 to M.P.C., from “La Caixa” Foundation (HR17-00231 to M.P.C.), NCI Outstanding Investigator award (R35 CA 197745 to A.C.), NIH Shared Instrumentation Grants (S10 OD012351, S10 OD021764, and S10OD032433, all to A.C.), NIH R01 (HD085904 and CA238005 to M.M.S), FI-AGAUR PhD fellowship from the Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and the co-finance of Fondo Social Europeo (2018FI_B_00637 and FSE to R.S.-P.), the Ramon y Cajal program of the Ministerio de Ciencia, Innovación y Universidades, and the European Social Fund (RYC-2018-025002-I to S.A.), and the Instituto de Salud Carlos III-FEDER (PI19/01814 to S.A.). We acknowledge support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the CERCA Programme/Generalitat de Catalunya.
dc.format.mimetype application/pdf
dc.identifier.citation Nakagawa S, Carnevali D, Tan X, Alvarez MJ, Parfitt DE, Di Vicino U, et al. The Wnt-dependent master regulator NKX1-2 controls mouse pre-implantation development. Stem Cell Reports. 2024 May 14;19(5):689-709. DOI: 10.1016/j.stemcr.2024.04.004
dc.identifier.doi http://dx.doi.org/10.1016/j.stemcr.2024.04.004
dc.identifier.issn 2213-6711
dc.identifier.uri http://hdl.handle.net/10230/61032
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Stem Cell Reports. 2024 May 14;19(5):689-709
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/964342
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86760-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-114080GB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2020-001049-S
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword NKX1-2
dc.subject.keyword RNA polymerase I
dc.subject.keyword Wnt signaling
dc.subject.keyword Embryonic stem cell
dc.subject.keyword Master regulator analysis
dc.subject.keyword Mouse embryo
dc.subject.keyword Nucleolus
dc.subject.keyword Ribosome biogenesis
dc.subject.keyword Systems biology
dc.title The Wnt-dependent master regulator NKX1-2 controls mouse pre-implantation development
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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