Cooperative epithelial phagocytosis enables error correction in the early embryo

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  • dc.contributor.author Hoijman, Esteban
  • dc.contributor.author Häkkinen, Hanna-Maria
  • dc.contributor.author Tolosa-Ramon, Queralt
  • dc.contributor.author Jiménez-Delgado, Senda
  • dc.contributor.author Wyatt, Christopher Douglas Robert, 1988-
  • dc.contributor.author Miret-Cuesta, Marta
  • dc.contributor.author Irimia Martínez, Manuel
  • dc.contributor.author Callan-Jones, Andrew
  • dc.contributor.author Wieser, Stefan
  • dc.contributor.author Ruprecht, Verena
  • dc.date.accessioned 2021-05-11T06:55:55Z
  • dc.date.issued 2021
  • dc.description.abstract Errors in early embryogenesis are a cause of sporadic cell death and developmental failure1,2. Phagocytic activity has a central role in scavenging apoptotic cells in differentiated tissues3-6. However, how apoptotic cells are cleared in the blastula embryo in the absence of specialized immune cells remains unknown. Here we show that the surface epithelium of zebrafish and mouse embryos, which is the first tissue formed during vertebrate development, performs efficient phagocytic clearance of apoptotic cells through phosphatidylserine-mediated target recognition. Quantitative four-dimensional in vivo imaging analyses reveal a collective epithelial clearance mechanism that is based on mechanical cooperation by two types of Rac1-dependent basal epithelial protrusions. The first type of protrusion, phagocytic cups, mediates apoptotic target uptake. The second, a previously undescribed type of fast and extended actin-based protrusion that we call 'epithelial arms', promotes the rapid dispersal of apoptotic targets through Arp2/3-dependent mechanical pushing. On the basis of experimental data and modelling, we show that mechanical load-sharing enables the long-range cooperative uptake of apoptotic cells by multiple epithelial cells. This optimizes the efficiency of tissue clearance by extending the limited spatial exploration range and local uptake capacity of non-motile epithelial cells. Our findings show that epithelial tissue clearance facilitates error correction that is relevant to the developmental robustness and survival of the embryo, revealing the presence of an innate immune function in the earliest stages of embryonic development.
  • dc.description.sponsorship Funding: Q.T.-R. acknowledges a grant funded by ‘The Ministerio de Ciencia, Innovación y Universidades and Fondo Social Europeo (FSE)’ (PRE2018-084393). M.I. acknowledges funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-StG-LS2-63759) and the Spanish Ministry of Economy and Competitiveness (BFU2014-55076-P). S.W. acknowledges support from the Government of Spain (MINECO’s Plan Nacional (PGC2018-098532-A-I00), Severo Ochoa (CEX2019- 000910-S) and Generalitat de Catalunya (CERCA, AGAUR). V.R. acknowledges support from the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and MINECO’s Plan Nacional (BFU2017-86296-P)
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Hoijman E, Häkkinen HM, Tolosa-Ramon Q, Jiménez-Delgado S, Wyatt C, Miret-Cuesta M et al. Cooperative epithelial phagocytosis enables error correction in the early embryo. Nature. 2021 Feb;590(7847):618-623. DOI: 10.1038/s41586-021-03200-3
  • dc.identifier.doi http://dx.doi.org/10.1038/s41586-021-03200-3
  • dc.identifier.issn 0028-0836
  • dc.identifier.uri http://hdl.handle.net/10230/47379
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature. 2021 Feb;590(7847):618-623
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/63759
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55076-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86296-P
  • dc.rights © Esteban Hoijman et al., under exclusive licence to Springer Nature Limited 2021
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.subject.other Embriologia
  • dc.subject.other Genètica
  • dc.subject.other Fagocitosi
  • dc.title Cooperative epithelial phagocytosis enables error correction in the early embryo
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/acceptedVersion

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