scholarly journals Yap Regulates Müller Glia Reprogramming in Damaged Zebrafish Retinas

2021 ◽  
Vol 9 ◽  
Author(s):  
Raquel Lourenço ◽  
Ana S. Brandão ◽  
Jorge Borbinha ◽  
Rita Gorgulho ◽  
António Jacinto
Keyword(s):  
Progenitor Cell ◽  
Hippo Pathway ◽  
Cell Formation ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell Cycle Reentry ◽  
Bona Fide ◽  
Reprogramming Factors ◽  
The Hippo Pathway ◽  
Dependent Mechanism

Vertebrates such as zebrafish have the outstanding ability to fully regenerate their retina upon injury, while mammals, including humans, do not. In zebrafish, upon light-induced injury, photoreceptor regeneration is achieved through reprogramming of Müller glia cells, which proliferate and give rise to a self-renewing population of progenitors that migrate to the lesion site to differentiate into the new photoreceptors. The Hippo pathway effector YAP was recently implicated in the response to damage in the retina, but how this transcription coactivator is integrated into the signaling network regulating Müller glia reprogramming has not yet been explored. Here, we show that Yap is required in Müller glia to engage their response to a lesion by regulating their cell cycle reentry and progenitor cell formation, contributing to the differentiation of new photoreceptors. We propose that this regulation is accomplished through a lin28a–ascl1a-dependent mechanism, bona fide Müller glia-reprogramming factors. Overall, this study presents Yap as a key regulator of zebrafish Müller glia reprogramming and consequently retina regeneration upon injury.

scholarly journals Linking YAP to Müller glia quiescence exit in the degenerative retina

2018 ◽  
Author(s):  
Annaïg Hamon ◽  
Divya Ail ◽  
Diana García-García ◽  
Juliette Bitard ◽  
Deniz Dalkara ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hippo Pathway ◽  
Müller Cells ◽  
Muller Glia ◽  
Muller Cells ◽  
Müller Glia ◽  
Egfr Signaling ◽  
Cell Cycle Genes ◽  
Retinal Injury ◽  
The Hippo Pathway

AbstractContrasting with fish or amphibian, retinal regeneration from Müller glial cells is largely limited in mammals. In our quest towards the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP, which we previously found to be upregulated in Müller cells following retinal injury. We report that conditional Yap deletion in Müller cells prevents the upregulation of cell cycle genes that normally accompanies reactive gliosis upon photoreceptor cell death. This occurs as a consequence of defective EGFR signaling. Consistent with a function of YAP in triggering Müller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injury-dependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Müller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Müller cell response to injury and highlight a novel YAP-EGFR axis by which Müller cells exit their quiescence state, a critical step towards regeneration.

scholarly journals SOX2 maintains the quiescent progenitor cell state of postnatal retinal Muller glia

Development ◽  
2013 ◽  
Vol 140 (7) ◽  
pp. 1445-1456 ◽  
Author(s):  
N. Surzenko ◽  
T. Crowl ◽  
A. Bachleda ◽  
L. Langer ◽  
L. Pevny
Keyword(s):  
Progenitor Cell ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell State

scholarly journals MINDY1 promotes bladder cancer progression by stabilizing YAP

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yongwen Luo ◽  
Jun Zhou ◽  
Jianing Tang ◽  
Fengfang Zhou ◽  
Zhiwen He ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Tumor Model ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Bona Fide ◽  
The Hippo Pathway

Abstract Background Bladder cancer is one of the most commonly diagnosed urological malignant tumor. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in bladder cancer remains to be characterized. Methods Western blot was used to measure the expression of MINDY1 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect the cell viability. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between MINDY1 and YAP. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results In the present study, we identified MINDY1, a DUB enzyme in the motif interacting with ubiquitin-containing novel DUB family, as a bona fide deubiquitylase of YAP in bladder cancer. MINDY1 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased bladder cancer cell proliferation. The effects induced by MINDY1 depletion could be rescued by further YAP overexpression. Depletion of MINDY1 decreased the YAP protein level and the expression of YAP/TEAD target genes in bladder cancer, including CTGF, ANKRD1 and CYR61. Conclusion In general, our findings establish a previously undocumented catalytic role for MINDY1 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of bladder cancer.

scholarly journals mTORC1-induced retinal progenitor cell overproliferation leads to accelerated mitotic aging and degeneration of descendent Müller glia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Soyeon Lim ◽  
You-Joung Kim ◽  
Sooyeon Park ◽  
Ji-heon Choi ◽  
Younghoon Sung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Tuberous Sclerosis Complex ◽  
Progenitor Cell ◽  
Mouse Retina ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Progenitor ◽  
Mechanistic Target Of Rapamycin ◽  
Glycolytic Gene

Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

scholarly journals Lats2 promotes heart failure by stimulating p53-mediated apoptosis during pressure overload

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dan Shao ◽  
Peiyong Zhai ◽  
Chengchen Hu ◽  
Risa Mukai ◽  
Sebastiano Sciarretta ◽  
...  
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Hippo Pathway ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Response To Stress ◽  
The Hippo Pathway ◽  
Dependent Mechanism

AbstractThe Hippo pathway plays a wide variety of roles in response to stress in the heart. Lats2, a component of the Hippo pathway, is phosphorylated by Mst1/2 and, in turn, phosphorylates YAP, causing inactivation of YAP. Lats2 stimulates apoptosis and negatively affects hypertrophy in cardiomyocytes. However, the role of Lats2 during cardiac stress is poorly understood in vivo. Lats2 is activated in the mouse heart in response to transverse aortic constriction (TAC). We used systemic Lats2 +/- mice to elucidate the role of endogenous Lats2. Cardiac hypertrophy and dysfunction induced by 4 weeks of TAC were attenuated in Lats2 +/- mice, and interstitial fibrosis and apoptosis were suppressed. Although TAC upregulated the Bcl-2 family proapoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-xL) molecules in non-transgenic mice, TAC-induced upregulation of Bax and Bak was alleviated and that of Bcl-2 was enhanced in Lats2 +/- mice. TAC upregulated p53, but this upregulation was abolished in Lats2 +/- mice. Lats2-induced increases in apoptosis and decreases in survival in cardiomyocytes were inhibited by Pifithrin-α, a p53 inhibitor, suggesting that Lats2 stimulates apoptosis via a p53-dependent mechanism. In summary, Lats2 is activated by pressure overload, thereby promoting heart failure by stimulating p53-dependent mechanisms of cell death.

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