Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear
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- dc.contributor.author Petrovic, Jelena, 1983-ca
- dc.contributor.author Formosa Jordán, Pauca
- dc.contributor.author Luna Escalante, Juan C.ca
- dc.contributor.author Abelló Sumpsi, Gina, 1980-ca
- dc.contributor.author Ibañes, Martaca
- dc.contributor.author Neves, Joanaca
- dc.contributor.author Giráldez, Fernandoca
- dc.date.accessioned 2016-02-26T10:19:28Z
- dc.date.available 2016-02-26T10:19:28Z
- dc.date.issued 2014ca
- dc.description.abstract During inner ear development, Notch exhibits two modes of operation: lateral induction, which is associated with prosensory specification, and lateral inhibition, which is involved in hair cell determination. These mechanisms depend respectively on two different ligands, jagged 1 (Jag1) and delta 1 (Dl1), that rely on a common signaling cascade initiated after Notch activation. In the chicken otocyst, expression of Jag1 and the Notch target Hey1 correlates well with lateral induction, whereas both Jag1 and Dl1 are expressed during lateral inhibition, as are Notch targets Hey1 and Hes5. Here, we show that Jag1 drives lower levels of Notch activity than Dl1, which results in the differential expression of Hey1 and Hes5. In addition, Jag1 interferes with the ability of Dl1 to elicit high levels of Notch activity. Modeling the sensory epithelium when the two ligands are expressed together shows that ligand regulation, differential signaling strength and ligand competition are crucial to allow the two modes of operation and for establishing the alternate pattern of hair cells and supporting cells. Jag1, while driving lateral induction on its own, facilitates patterning by lateral inhibition in the presence of Dl1. This novel behavior emerges from Jag1 acting as a competitive inhibitor of Dl1 for Notch signaling. Both modeling and experiments show that hair cell patterning is very robust. The model suggests that autoactivation of proneural factor Atoh1, upstream of Dl1, is a fundamental component for robustness. The results stress the importance of the levels of Notch signaling and ligand competition for Notch function.
- dc.description.sponsorship The work was supported by grants from Ministerio de Ciencia e Innovacion (MICINN)/n[BFU-2011-24057, PLE-2009-0098, FIS2012-37655-C02-02] and Generalitat de/nCatalunya (GENCAT) [2009SGR14], Spain; fellowships SFRH/BPD/70691/2010 to/nJ.N. from Fundação para a Ciência e a Tecnologia (FCT), Portugal; FPU-AP2008-/n03325 to P.F.-J. from Ministerio de Educación (MEC); and BES-2009-022286 to J.P./nfrom MICINN, Spain
- dc.format.mimetype application/pdfca
- dc.identifier.citation Petrovic J, Formosa-Jordan P, Luna-Escalante JC, Abelló G, Ibañes M, Neves J et al. Ligand-dependent Notch signaling strength orchestrates lateral/ninduction and lateral inhibition in the developing inner ear. Development. 2014 Jun; 141(11): 2313-24. DOI: 10.1242/dev.108100ca
- dc.identifier.doi http://dx.doi.org/10.1242/dev.108100
- dc.identifier.issn 0950-1991ca
- dc.identifier.uri http://hdl.handle.net/10230/25954
- dc.language.iso engca
- dc.publisher Company of Biologistsca
- dc.relation.ispartof Development. 2014 Jun;141(11):2313-24
- dc.rights © Company of Biologists http://dx.doi.org/10.1242/dev.108100ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.subject.other Cèl·lules acústiques
- dc.subject.other Oïda -- Desenvolupament
- dc.subject.other Embriologia
- dc.title Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner earca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/acceptedVersionca