Deficiency of Yes-Associated Protein Induces Cataract in Mice

He, Qing; Gao, Yuhao; Wang, Tongxing; Zhou, Lujun; Zhou, Wenxia; Yuan, Zengqiang

doi:10.14336/ad.2018.0910

Cited by 14 publications

(16 citation statements)

References 49 publications

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“…Abnormal reactive astrogliosis and microglial activation are observed in YAP knockout mice during cerebral development. Hence, astroglial YAP deletion leads to excessive activation of inflammatory pathways, which potentiates the proinflammatory effects of reactive astrogliosis [ 32 , 63 ]. YAP has also been shown to play an important role in regulating cellular junctions.…”

Section: Discussionmentioning

confidence: 99%

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Cao

et al. 2020

J Neuroinflammation

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Background In the central nervous system (CNS), connexin 43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Similar to Cx43 overexpression, abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies. However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear. Methods Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH models in vitro and in vivo. After ICH injury, the Cx43 mimetic peptide Gap19 was used for treatment. Ethidium bromide (EtBr) uptake assays were used to measure the opening of Cx43Hcs. Western blotting and immunofluorescence were used to measure protein expression. qRT-PCR and ELISA were used to determine the levels of cytokines. Coimmunoprecipitation (Co-IP) and the Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins. Results In this study, Cx43 expression upregulation and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19 significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition, Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture. However, Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased Yes-associated protein (YAP) nuclear translocation. This subsequently upregulated SOCS1 and SOCS3 expression and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor, verteporfin (VP), reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury. Conclusions This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs. Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 has anti-inflammatory and neuroprotective effects after ICH injury.

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Section: Discussionmentioning

confidence: 99%

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Cao

et al. 2020

J Neuroinflammation

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“…A recent study also showed that Yap1 conditional knockout mice developed cataracts with reduced LEC proliferation, however whether or not the LEC apoptosis had also been affected was not clear. 31 From a therapeutic perspective, inhibition of YAP1 activity could potentially be used as an anti-cancer therapy to limit both cancer growth and metastasis. 56 Our finding on the regulation of adult lens homeostasis by YAP1 expression highlights the importance of balancing Yap1 activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

“… 30 Yap activity is essential for maintenance of LEC progenitor activity by preserving self-renewal, and inhibiting apoptosis and precocious differentiation. 31 , 32 In addition, Yap plays a crucial role in maintaining LEC and fiber morphology via stabilizing apical polarity complex and junctional proteins. 32 Inhibition of YAP with Verteporfin suppressed FGF-induced lens cell proliferation and ablated cell elongation during lens fiber differentiation.…”

mentioning

confidence: 99%

Heterozygous Loss of Yap1 in Mice Causes Progressive Cataracts

Zhang

Kasetti

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose Yap1 encodes an evolutionarily conserved transcriptional coactivator and functions as a down-stream effector of the Hippo signaling pathway that controls tissue size and cell growth. Yap1 contributes to lens epithelial development. However, the effect of Yap1 haplodeficiency on the lens epithelium and its role in the development of cataracts has not been reported. The aim of the current study is to investigate Yap1 function and its regulatory mechanisms in lens epithelial cells (LECs). Methods Lens phenotypes were investigated in Yap1 heterozygous mutant mice by visual observation and histological and biochemical methods. Primary LEC cultures were used to study regulatory molecular mechanism. Results The heterozygous inactivation of Yap1 in mice caused cataracts during adulthood with defective LEC phenotypes. Despite a normal early development of the eye including the lens, the majority of Yap1 heterozygotes developed cataracts in the first six months of age. Cataract was preceded by multiple morphological defects in the lens epithelium, including decreased cell density and abnormal cell junctions. The low LEC density was coincident with reduced LEC proliferation. In addition, expression of the Yap1 target gene Crim1 was reduced in the Yap1 +/ − LEC, and overexpression of Crim1 restored Yap1 +/ − LEC cell proliferation in vitro. Conclusions Homozygosity of the Yap1 gene was critical for adequate Crim1 expression needed to maintain the constant proliferation of LEC and to maintain a normal - sized lens. Yap1 haplodeficiency leads to cataracts.

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“…Recently, the functions of YAP signaling in astrocytes were evaluated. Abnormal reactive astrogliosis and microglial activation are observed in YAP knockout mice during cerebral development.Hence,astroglial YAP deletion leads to excessive activation of in ammatory pathways, which seems to aggravate dysfunction of astrocytes and the proin ammatory effects of reactive astrogliosis [28,63].Interestingly,YAP has been shown to play an important role in regulating cellular junctions. Inhibition of its transcriptional activity at the plasma membrane can disrupt cellular contacts [64].Yang et al found that astrocytic Cx43 reduces the nuclear translocation of YAP in a hemoglobin mouse model [27].…”

Section: Discussionmentioning

confidence: 99%

Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Cao

et al. 2020

Preprint

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Background: In the central nervous system(CNS),Connexin43 (Cx43) is mainly expressed in astrocytes and regulates astrocytic network homeostasis. Like Cx43 overexpression,abnormal excessive opening of Cx43 hemichannels (Cx43Hcs) on reactive astrocytes aggravates the inflammatory response and cell death in CNS pathologies.However, the role of excessive Cx43Hc opening in intracerebral hemorrhage (ICH) injury is not clear.Methods: Hemin stimulation in primary cells and collagenase IV injection in C57BL/6J (B6) mice were used as ICH modals in vitro and vivo.Cx43 mimetic peptide Gap19 was treated after ICH injury. Ethidium bromide (EtBr) uptake assays was used to measure the opening of Hcs. Western blot and immunofluorescence were used to measure the expression of protein. qRT-PCR and ELISA were used to determine the level of cytokines. Co-immunoprecipitation(Co-IP) and Duolink in situ proximity ligation assay (PLA) were applied to measure the association between proteins.Results: In this study,Cx43 expression was upregulated, and excessive Cx43Hc opening was observed in mice after ICH injury. Delayed treatment with Gap19significantly alleviated hematoma volume and neurological deficits after ICH injury. In addition,Gap19 decreased inflammatory cytokine levels in the tissue surrounding the hematoma and decreased reactive astrogliosis after ICH injury in vitro and in vivo, as determined by GFAP staining. Intriguingly, Cx43 transcriptional activity and expression in astrocytes were significantly increased after hemin stimulation in culture.However,Gap19 treatment downregulated astrocytic Cx43 expression through the ubiquitin-proteasome pathway without affecting Cx43 transcription. Additionally, our data showed that Gap19 increased YAP nuclear translocation, which upregulated SOCS1 and SOCS3 expression, and then inhibited the TLR4-NFκB and JAK2-STAT3 pathways in hemin-stimulated astrocytes. Finally, the YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of Gap19 in vitro and almost completely blocked its protective effects in vivo after ICH injury.Conclusions: This study provides new insight into potential treatment strategies for ICH injury involving astroglial Cx43 and Cx43Hcs.Suppression of abnormal astroglial Cx43 expression and Cx43Hc opening by Gap19 plays anti-inflammatory and neuroprotective roles after ICH injury.

show abstract

Deficiency of Yes-Associated Protein Induces Cataract in Mice

Cited by 14 publications

References 49 publications

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

Heterozygous Loss of Yap1 in Mice Causes Progressive Cataracts

Targeting Connexin43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling

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