A growing role for the Hippo signaling pathway in the heart

Zhang, Yu; Re, Dominic P. Del

doi:10.1007/s00109-017-1525-5

Cited by 26 publications

(20 citation statements)

References 70 publications

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“…We next sought to understand the molecular mechanisms supporting ephrin-B1 as a suppressor of adult CM proliferation. Given its importance in the control of CM proliferation 32 , we examined the Hippo pathway in the 2-month-old efnb1 cKO mice and more specifically its core effector, Yap1. Yap1 gene (Figure 6A) or Yap1 protein expression and activity (phosphorylation state, P-Yap) (Figure 6B; specificity of Yap1 immunostaining in western-blot was assessed as shown in Supplementary material online, Figure S10) were similar in CMs from resting young cKO or WT mice, with predominance of inactive P-Yap1, thus corroborating the absence of constitutive CM proliferation in efnb1 cKO mice at resting state.…”

Section: Ephrin-b1 Sequesters Yap1 At the Lateral Membrane To Preventmentioning

confidence: 99%

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Cauquil

Mias

Guilbeau‐Frugier

et al. 2019

Preprint

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Aims.Deciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration. Methods and results:Transgenic-or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the postmitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferation Conclusions:Our results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment. SignificanceThe mammalian adult heart is unable to regenerate due to the inability of cardiomyocytes (CMs) to proliferate and replace cardiac tissue lost. Exploiting CM-specific transgenic mice or AAV9-based gene therapy, this works identifies ephrin-B1, a specific rod-shape stabilizer of the adult CM, as a natural padlock of adult CM proliferation for compensatory adaptation to different cardiac stresses (apectomy, MI, senescence), thus emphasizing a new link between the adult CM morphology and their proliferation potential. Moreover, the study demonstrates proof-of-concept that targeting ephrin-B1 may be an innovative therapeutic approach for ischemic heart failure. MethodsDetailed materials and methods are provided in the Supplementary material online.Animal models. Global (KO) and CM-specific (cKO) efnb1 KO mice have already been described 23 . Efnb1 WT and KO mice were kept in a mixed S129/S4 × C57BL/6 background. All studies were performed on male and age-matched mice. Experimental animal protocols were carried out in accordance with the French regulation guidelines for animal experimentation and were approved by the French CEEA-122 ethical committee.Data analysis. The n number for each experiment and analysis are stated in each figure legend. All bar graphs, except fo...

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Section: Ephrin-b1 Sequesters Yap1 At the Lateral Membrane To Preventmentioning

confidence: 99%

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Cauquil

Mias

Guilbeau‐Frugier

et al. 2019

Preprint

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“…Although according to Zhang et al, 44,45 the method based on steady-state DFT would be more accurate for the current calculation than the method based on DFT+NEGF. But they yield very similar I-V (current-voltage) curves.…”

Section: Computational Detailsmentioning

confidence: 99%

Effects of line defects on spin-dependent electronic transport of zigzag MoS2 nanoribbons

Cui

Yang

et al. 2016

AIP Advances

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The nonlinear spin-dependent transport properties in zigzag molybdenum-disulfide nanoribbons (ZMNRs) with line defects are investigated systematically using nonequilibrium Green’s function method combined with density functional theory. The results show that the line defects can enhance the electronic transfer ability of ZMNRs. The types and locations of the line defects are found critical in determining the spin polarization and the current-voltage (I-V) characteristics of the line defected ZMNRs. For the same defect type, the total currents of the ribbons with the line defects in the centers are lager than those on the edges. And for the same location, the total currents of the systems with the sulfur (S) line defect are larger than the according systems with the molybdenum (Mo) line defect. All the considered systems present magnetism properties. And in the S line defected systems, the spin reversal behaviors can be observed. In both the spin-up and spin-down states of the Mo line defected systems, there are obvious negative differential resistance behaviors. The mechanisms are proposed for these phenomena.

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“…Recent evidence also implicates the relatively less-well-characterized Hippo pathway as a major signaling pathway governing the cellular response to diverse physiological stimuli (Harvey et al, 2013 ; Meng et al, 2016 ). The role of the Hippo pathway in Drosophila (Richardson and Portela, 2017 ), during early mammalian developmental stages (Sasaki, 2017 ), or in specific tissues such as the heart (He et al, 2017 ; Zhang and Del Re, 2017 ), intestine (Gregorieff and Wrana, 2017 ), and liver (Patel et al, 2017 ) have recently been described. In this review, we aim to provide the reader with an outline of the critical elements that form the core Hippo signaling pathway in mammals, and to describe the experimental evidence supporting a vital role for this pathway as a major regulator of tissue growth and differentiation in response to three main forms of external regulation: hormonal, mechanical and metabolic stimuli.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway

2017

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The integrative control of diverse biological processes such as proliferation, differentiation, apoptosis and metabolism is essential to maintain cellular and tissue homeostasis. Disruption of these underlie the development of many disease states including cancer and diabetes, as well as many of the complications that arise as a consequence of aging. These biological outputs are governed by many cellular signaling networks that function independently, and in concert, to convert changes in hormonal, mechanical and metabolic stimuli into alterations in gene expression. First identified in Drosophila melanogaster as a powerful mediator of cell division and apoptosis, the Hippo signaling pathway is a highly conserved regulator of mammalian organ size and functional capacity in both healthy and diseased tissues. Recent studies have implicated the pathway as an effector of diverse physiological cues demonstrating an essential role for the Hippo pathway as an integrative component of cellular homeostasis. In this review, we will: (a) outline the critical signaling elements that constitute the mammalian Hippo pathway, and how they function to regulate Hippo pathway-dependent gene expression and tissue growth, (b) discuss evidence that shows this pathway functions as an effector of diverse physiological stimuli and (c) highlight key questions in this developing field.

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A growing role for the Hippo signaling pathway in the heart

Cited by 26 publications

References 70 publications

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

Effects of line defects on spin-dependent electronic transport of zigzag MoS2 nanoribbons

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway

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