title: The Hippo pathway member Nf2 is required for inner cell mass specification.
abstract: During mammalian development, the first two lineages to be specified are the trophectoderm (TE) and the inner cell mass (ICM). The Hippo pathway kinases Lats 1 and 2 (Lats1/2) and the transcriptional coactivator Yap play important roles in this specification process [1]. In outside cells of the embryo, Yap is nuclear localized and cooperates with Tead4 to induce the TE-specifying transcription factor Cdx2. In inside cells, Lats1/2 phosphorylate Yap and prevent its nuclear localization. The factors acting upstream of Lats1/2 and Yap in this context have not been identified. Here, we demonstrate that the upstream Hippo pathway member Nf2/Merlin is required for Lats1/2-dependent Yap phosphorylation in the preimplantation embryo. Injection of dominant-negative Nf2 mRNA causes Yap mislocalization and ectopic Cdx2 expression, effects that can be rescued by overexpression of Lats2 kinase. Zygotic Nf2 mutant blastocysts have mild defects in Yap localization and Cdx2 expression, but these become much more severe upon removal of both maternal and zygotic Nf2. The inside cells of maternal-zygotic mutants fail to establish a pluripotent ICM and form excess TE, resulting in peri-implantation lethality. Together, these data establish a clear role for Nf2 upstream of Yap in the preimplantation embryo and demonstrate that Hippo signaling is essential to segregate the ICM from the TE.
authors.affiliation: Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.
authors.forename: Katie
authors.initials: K
authors.lastname: Cockburn
authors.forename: Steffen
authors.initials: S
authors.lastname: Biechele
authors.forename: Jodi
authors.initials: J
authors.lastname: Garner
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D018797:Cell Cycle Proteins; D018507:Gene Expression Regulation, Developmental; D000090683:Hippo Signaling Pathway; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D025581:Neurofibromin 2 / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases