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 neural crest, which is critical 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 may be relevant to the function of these signaling cascades in many tissues and in diseases such as cancer.

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

“…Notch ligand binding induces sequential proteolytic cleavage of Notch receptors to generate Notch intracellular domain (NICD) (45), which enters the nucleus to participate in the transcriptional regulation of target genes (46)(47)(48). As with previous studies (49,50), the expression of jagged 1 (Jag1), which encodes the Notch ligand JAG1, and Notch genes were upregulated in the DKO liver ( Figure 1A and Supplemental Figure 1, A and B; supplemental material available online with this article; doi:10.1172/JCI88486DS1). We then examined Notch signaling activities directly and found that Notch reporter activity, NICD Data are expressed as the mean ± SEM.…”

“…Similarly, Jag1 induction by YAP/TAZ and NICD interaction could also be tissue context dependent. While 2 TEAD response elements in the JAG1 promoter and the YAP/TEAD complex were found to be essential for JAG1 induction in HCC cells (49), YAP has also been found to require NICD to induce Jag1 expression in an RBP-Jκ-dependent, but TEAD-independent, fashion in smooth muscle cells (50).…”

Excitable Dynamics and Yap-Dependent Mechanical Cues Drive the Segmentation Clock

“…when the system is above the excitability threshold as when lowering Yap signaling for instance), Notch signaling would only be needed to synchronize oscillators. These effects might result in part from Yap interacting with Notch signaling as demonstrated in other systems (Manderfield et al, 2015; Totaro et al, 2017). Since the cyclic activity induced by LatA treatment was observed independently of γ-secretase activity, it raises the question of the pacemaker controlling Lfng oscillations, as this gene is considered a direct Notch target (Morales et al, 2002).…”

Yap and Taz play a crucial role in neural crest-derived craniofacial development

“…4). A recent study indicated that Yap and Taz deficiency gives rise to smooth muscle differentiation defects partially derived from the CNC (Manderfield et al, 2015). Given the similar vessel defects in Wnt1…”