scholarly journals YAP is involved in replenishment of granule cell progenitors following injury to the neonatal cerebellum

2019 ◽  
Author(s):  
Zhaohui Yang ◽  
Alexandra L. Joyner
Keyword(s):  
Granule Cell ◽  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Initial Step ◽  
Granule Cell Layer ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Full Spectrum

ABSTRACTThe cerebellum (CB) undergoes major rapid growth during the third trimester and early neonatal stage in humans, making it vulnerable to injuries in pre-term babies. Experiments in mice have revealed a remarkable ability of the neonatal CB to recover from injuries around birth. In particular, recovery following irradiation-induced ablation of granule cell precursors (GCPs) involves adaptive reprogramming of Nestin-expressing glial progenitors (NEPs). Sonic hedgehog signaling is required for the initial step in NEP reprogramming; however, the full spectrum of developmental signaling pathways that promote NEP-driven regeneration is not known. Since the growth regulatory Hippo pathway has been implicated in the repair of several tissue types, we tested whether Hippo signaling is involved in regeneration of the CB. Using mouse models, we found that the Hippo pathway transcriptional co-activator YAP (Yes-associated protein) but not TAZ (transcriptional coactivator with PDZ binding motif) is required in NEPs for full recovery of the CB following irradiation one day after birth. The size of the adult CB, and in particular the internal granule cell layer produced by GCPs, is significantly reduced in mutants, and the organization of Purkinje cells and Bergmann glial fibers is disrupted. Surprisingly, the initial proliferative response of Yap mutant NEPs to irradiation is normal and the cells migrate to the GCP niche, but then undergo increased cell death. Loss of Yap in NEPs or GCPs during normal development leads to only mild defects in differentiation. Moreover, loss of Taz does not abrogate regeneration of GCPs by Yap mutant NEPs or alter development of the cerebellum. Our study provides new insights into the molecular signaling underlying postnatal cerebellar development and regeneration.

scholarly journals EGF Receptor–Dependent YAP Activation Is Important for Renal Recovery from AKI

2018 ◽  
Vol 29 (9) ◽  
pp. 2372-2385 ◽  
Author(s):  
Jianchun Chen ◽  
Huaizhou You ◽  
Yan Li ◽  
You Xu ◽  
Qian He ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Cycle Progression ◽  
Egf Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hippo Pathway ◽  
Critical Role ◽  
Renal Recovery ◽  
Binding Motif ◽  
Hippo Signaling

BackgroundIncreasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI.MethodsWe used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap, Taz, or both occurring specifically in RPTCs) that were subjected to bilateral IRI.ResultsYAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression.ConclusionsThis study shows that EGFR-PI3K-Akt–dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.

scholarly journals The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anke Hermann ◽  
Guangming Wu ◽  
Pavel I. Nedvetsky ◽  
Viktoria C. Brücher ◽  
Charlotte Egbring ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Cell Fate ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Large Tumor ◽  
Organ Growth ◽  
The Hippo Pathway

AbstractThe WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina. In summary, our data elucidate a novel role for Wwc2 as a key regulator in early embryonic development and sprouting angiogenesis in mice.

scholarly journals A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Ellen C. Gingrich ◽  
Kendra Case ◽  
A. Denise R. Garcia
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Adult Brain ◽  
Substantial Contribution ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Independent Manner ◽  
Shh Signaling ◽  
Cortical Astrocyte

Abstract Background The molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. However, Shh activity is found in discrete subpopulations of astrocytes in the postnatal and adult brain. Whether Shh signaling plays a role in astrocyte development is not well understood. Methods Here, we use a genetic inducible fate mapping approach to mark and follow a population of glial progenitor cells expressing the Shh target gene, Gli1, in the neonatal and postnatal brain. Results In the neonatal brain, Gli1-expressing cells are found in the dorsolateral corner of the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Our data show that these cells give rise to half of the cortical astrocyte population, demonstrating their substantial contribution to the cellular composition of the cortex. Further, these data suggest that the cortex harbors astrocytes from different lineages. Gli1 lineage astrocytes are distributed across all cortical layers, positioning them for broad influence over cortical circuits. Finally, we show that Shh activity recurs in mature astrocytes in a lineage-independent manner, suggesting cell-type dependent roles of the pathway in driving astrocyte development and function. Conclusion These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.

scholarly journals Hippo Pathway in Regulating Drug Resistance of Glioblastoma

2021 ◽  
Vol 22 (24) ◽  
pp. 13431
Author(s):  
Giacomo Casati ◽  
Laura Giunti ◽  
Anna Lisa Iorio ◽  
Arianna Marturano ◽  
Luisa Galli ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Pathway Activation ◽  
Promising Target ◽  
Kinase Cascade ◽  
Tumor Immunosuppression ◽  
The Central Nervous System ◽  
Immunosuppressive Microenvironment ◽  
The Hippo Pathway

Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.

scholarly journals Hepatic Hippo signaling inhibits development of hepatocellular carcinoma

2020 ◽  
Vol 26 (4) ◽  
pp. 742-750
Author(s):  
Yuchen Liu ◽  
Xiaohui Wang ◽  
Yingzi Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Hippo Pathway ◽  
Hepatocyte Proliferation ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Human Liver Cancer ◽  
Kinase Cascade ◽  
The Hippo Pathway

Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.

scholarly journals Sonic hedgehog signaling in astrocytes

2020 ◽  
Author(s):  
Steven A. Hill ◽  
Marissa Fu ◽  
A. Denise R. Garcia
Keyword(s):  
Nervous System ◽  
Signaling Pathway ◽  
Functional Properties ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Synapse Formation ◽  
Synaptic Activity ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling

Abstract Astrocytes are complex cells that perform a broad array of essential functions in the healthy and injured nervous system. The recognition that these cells are integral components of various processes, including synapse formation, modulation of synaptic activity, and response to injury, underscores the need to identify the molecular signaling programs orchestrating these diverse functional properties. Emerging studies have identified the Sonic hedgehog (Shh) signaling pathway as an essential regulator of the molecular identity and functional properties of astrocytes. Well established as a powerful regulator of diverse neurodevelopmental processes in the embryonic nervous system, its functional significance in astrocytes is only beginning to be revealed. Notably, Shh signaling is active only in discrete subpopulations of astrocytes distributed throughout the brain, a feature that has potential to yield novel insights into functional specialization of astrocytes. Here, we discuss Shh signaling and emerging data that point to essential roles for this pleiotropic signaling pathway in regulating various functional properties of astrocytes in the healthy and injured brain.

scholarly journals Hippo Signaling Pathway in Gliomas

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 184
Author(s):  
Konstantin Masliantsev ◽  
Lucie Karayan-Tapon ◽  
Pierre-Olivier Guichet
Keyword(s):  
Brain Tumors ◽  
Signaling Pathway ◽  
Cancer Biology ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Central Nervous System Neoplasms ◽  
Hippo Signaling Pathway

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.

scholarly journals Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development

2017 ◽  
Vol 96 (11) ◽  
pp. 1229-1237 ◽  
Author(s):  
J. Wang ◽  
J.F. Martin
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Tooth Development ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
Evolutionarily Conserved ◽  
The Hippo Pathway

The evolutionarily conserved Hippo signaling pathway is a vital regulator of organ size that fine-tunes cell proliferation, apoptosis, and differentiation. A number of important studies have revealed critical roles of Hippo signaling and its effectors Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ binding motif) in tissue development, homeostasis, and regeneration, as well as in tumorigenesis. In addition, recent studies have shown evidence of crosstalk between the Hippo pathway and other key signaling pathways, such as Wnt signaling, that not only regulates developmental processes but also contributes to disease pathogenesis. In this review, we summarize the major discoveries in the field of Hippo signaling and what has been learned about its regulation and crosstalk with other signaling pathways, with a particular focus on recent findings involving the Hippo-Yap pathway in craniofacial and tooth development. New and exciting studies of the Hippo pathway are anticipated that will significantly improve our understanding of the molecular mechanisms of human craniofacial and tooth development and disease and will ultimately lead to the development of new therapies.

scholarly journals Mechanotransduction and Cytoskeleton Remodeling Shaping YAP1 in Gastric Tumorigenesis

2019 ◽  
Vol 20 (7) ◽  
pp. 1576 ◽  
Author(s):  
Jinglin Zhang ◽  
Yuhang Zhou ◽  
Patrick Tang ◽  
Alfred Cheng ◽  
Jun Yu ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Tumor Formation ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Therapeutic Value ◽  
Cytoskeleton Remodeling ◽  
Mechanical Sensor ◽  
The Hippo Pathway

The essential role of Hippo signaling pathway in cancer development has been elucidated by recent studies. In the gastrointestinal tissues, deregulation of the Hippo pathway is one of the most important driving events for tumorigenesis. It is widely known that Yes-associated protein 1 (YAP1) and WW domain that contain transcription regulator 1 (TAZ), two transcriptional co-activators with a PDZ-binding motif, function as critical effectors negatively regulated by the Hippo pathway. Previous studies indicate the involvement of YAP1/TAZ in mechanotransduction by crosstalking with the extracellular matrix (ECM) and the F-actin cytoskeleton associated signaling network. In gastric cancer (GC), YAP1/TAZ functions as an oncogene and transcriptionally promotes tumor formation by cooperating with TEAD transcription factors. Apart from the classic role of Hippo-YAP1 cascade, in this review, we summarize the current investigations to highlight the prominent role of YAP1/TAZ as a mechanical sensor and responder under mechanical stress and address its potential prognostic and therapeutic value in GC.

scholarly journals A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

2020 ◽  
Author(s):  
Ellen Gingrich ◽  
Kendra Case ◽  
A. Denise R. Garcia
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Cortical Astrocyte ◽  
Germinal Zone ◽  
The Central Nervous System ◽  
Oligodendrocyte Development

ABSTRACTThe molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. Here, we show that Shh signaling also operates in a subpopulation of progenitor cells that generate cortical astrocytes. In the neonatal brain, cells expressing the Shh target gene, Gli1, are found in the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Using a genetic inducible fate mapping strategy, we show that these cells give rise to half of the cortical astrocyte population, suggesting that the cortex harbors astrocytes from different lineages. Shh activity in SVZ progenitor cells is transient but recurs in a subpopulation of mature astrocytes localized in layers IV and V in a manner independent of their lineage. These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.

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