Hippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest

Development. 2015 Sep 1;142(17):2962-71. doi: 10.1242/dev.125807. Epub 2015 Aug 7.


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.

Keywords: Hippo signaling; Jagged1; Mouse; Neural crest; Notch signaling; Taz; Vascular development; Yap.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Aorta, Thoracic / metabolism
  • Cell Cycle Proteins
  • Cell Differentiation*
  • DNA-Binding Proteins / metabolism
  • Gene Deletion
  • HEK293 Cells
  • Humans
  • Mesoderm / metabolism
  • Mice
  • Muscle, Smooth / metabolism
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / metabolism*
  • Neural Crest / cytology*
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Notch / chemistry
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Phosphoproteins
  • Receptors, Notch
  • Taz protein, mouse
  • Tead1 protein, mouse
  • Transcription Factors
  • Yap1 protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases