title: Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest.
abstract: Notch signaling has well-defined roles in the assembly of arterial walls and in the development of the endothelium and smooth muscle of the vasculature. Hippo signaling regulates cellular growth in many tissues, and contributes to regulation of organ size, in addition to other functions. Here, we show that the Notch and Hippo pathways converge to regulate smooth muscle differentiation of the neural crest, which is crucial for normal development of the aortic arch arteries and cranial vasculature during embryonic development. Neural crest-specific deletion of the Hippo effectors Yap and Taz produces neural crest precursors that migrate normally, but fail to produce vascular smooth muscle, and Notch target genes such as Jagged1 fail to activate normally. We show that Yap is normally recruited to a tissue-specific Jagged1 enhancer by directly interacting with the Notch intracellular domain (NICD). The Yap-NICD complex is recruited to chromatin by the DNA-binding protein Rbp-J in a Tead-independent fashion. Thus, Hippo signaling can modulate Notch signaling outputs, and components of the Hippo and Notch pathways physically interact. Convergence of Hippo and Notch pathways by the mechanisms described here might be relevant for the function of these signaling cascades in many tissues and in diseases such as cancer.
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Manderfield
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Haig
authors.initials: H
authors.lastname: Aghajanian
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Engleka
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lillian Y
authors.initials: LY
authors.lastname: Lim
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Cell and Developmental Biology, The Cardiovascular Institute and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA epsteinj@mail.med.upenn.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009130:Muscle, Smooth / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D000091262:TEA Domain Transcription Factors; C083215:Tead1 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hippo signaling; Jagged1; Mouse; Neural crest; Notch signaling; Taz; Vascular development; Yap