Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size

Abstract

Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Transgenic expression of YAP caused unaltered progenitor cell compartment and no changes in the distribution of the hematopoietic lineages compared to control mice (Jansson and Larsson, 2012). Similarly, knockout of Sav1 in mouse heart leads to cardiomegaly due to abnormal proliferation of cardiomyocytes, but the number of cardiac progenitor cells remained normal (Heallen et al, 2011). Therefore, it would be important to further investigate the regulation, function, and specificity of the Hippo pathway in each organ in order to understand the role of the Hippo pathway in both differentiated cells and stem cells in organ development.…”

Hippo Pathway Effectors Control Cardiac Progenitor Cell Fate by Acting as Dynamic Sensors of Substrate Mechanics and Nanostructure

“…Interestingly, the Hippo pathway has been identified as a critical determinant of the organ size by controlling fetal cardiomyocyte proliferation, 21 through the IGF axis 22 or by inhibiting the Wnt/β-catenin signaling pathway. 23 Cardiomyocyte-specific YAP1 deletion in the fetal mouse heart causes lethal myocardial hypoplasia and a reduction in cardiomyocyte proliferation, while this factor appears to be dispensable for the postnatal physiological hypertrophy. 21 Cardiac tissue homeostasis throughout life is thought to depend on the proliferation and differentiation of resident stem/progenitor cells, 22 although their actual capacity to enhance organ function is still debated.…”

« Le monde selon YAP »

“…Ces deux travaux révèlent donc un rôle cytoplasmique des protéines YAP et TAZ qui limitent l'activation nucléaire de la β-caténine. Un troisième niveau d'action, synergique cette fois, a été décrit dans le coeur et les cellules cancéreuses coliques où les protéines YAP et β-caténine, une fois dans le noyau, sont recrutées sur des cibles communes comme SOX2 ou la cycline D1 [6] ( Figure 2). Il n'a pas encore été démontré, néanmoins, que la protéine YAP non phosphorylée était capable de faciliter le transport nucléaire de la β-caténine.…”

“…Deux travaux récents publiés dos-à-dos dans la revue Cell en décembre 2012 inversent les rôles et suggèrent que la voie Wnt contrôle à son tour la voie Hippo-Mst. L'équipe italienne de Piccolo démontre que le ligand Wnt3a induit l'accumulation de la protéine TAZ, faisant de cette protéine un second messager de la voie Wnt au même titre que la β-caténine [6]. Ces résultats rappellent des travaux antérieurs qui, par immunopré-cipitation de chromatine, avaient identifié des sites de liaison du complexe β-caténine/TCF dans un intron du gène YAP dans des cellules de cancer colorectal [8].…”