Inhibition of Lats1/p‐<scp>YAP</scp>1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury

Li, Di; Ji, Jiaxuan; Xu, Yitian; Ni, Haibo; Qin, Rui; Liu, Huixiang; Jiang, Feng; Gao, Rong; Chen, Gang

doi:10.1111/cns.12833

Cited by 18 publications

(7 citation statements)

References 33 publications

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“…Most studies on YAP previously focused on tumorigenesis, since the upregulation of YAP promotes cell growth and inhibits apoptosis of tumor cells (Lau et al, 2014;Zanconato et al, 2016). For CNS injuries, MST1 and LATS1 have detrimental effects on neural recovery after traumatic brain injury and SCI (M. Li et al, 2018;Qu et al, 2018;. Our recent studies indicate that YAP participates in astrocytic differentiation of the developing mouse cortex via BMP2-YAP-SMAD1 pathway (Huang et al, 2016b).…”

Section: Introductionmentioning

confidence: 90%

Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury

Xie

Shen

et al. 2020

J. Neurosci.

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Yes-associated protein (YAP) transcriptional coactivator is negatively regulated by the Hippo pathway and functions in controlling the size of multiple organs, such as liver during development. However, it is not clear whether YAP signaling participates in the process of the formation of glia scars after spinal cord injury (SCI). In this study, we found that YAP was upregulated and activated in astrocytes of C57BL/6 male mice after SCI in a Hippo pathway-dependent manner. Conditional knockout (KO) of yap in astrocytes significantly inhibited astrocytic proliferation, impaired the formation of glial scars, inhibited the axonal regeneration, and impaired the behavioral recovery of C57BL/6 male mice after SCI. Mechanistically, the bFGF was upregulated after SCI and induced the activation of YAP through RhoA pathways, thereby promoting the formation of glial scars. Additionally, YAP promoted bFGF-induced proliferation by negatively controlling nuclear distribution of p27 Kip1 mediated by CRM1. Finally, bFGF or XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) injection indeed activated YAP signaling and promoted the formation of glial scars and the functional recovery of mice after SCI. These findings suggest that YAP promotes the formation of glial scars and neural regeneration of mice after SCI, and that the bFGF-RhoA-YAP-p27 Kip1 pathway positively regulates astrocytic proliferation after SCI.

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Section: Introductionmentioning

confidence: 90%

Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury

Xie

Shen

et al. 2020

J. Neurosci.

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“…Hyper-activation of Hippo signaling is associated with neuronal death in multiple forms of neurodegeneration including Huntington’s disease [ 89 , 90 , 91 ], amyotrophic lateral sclerosis (ALS) [ 92 ], traumatic brain injury [ 93 ], mild cognitive impairment (MCI), and AD [ 94 , 95 ], while inhibition of Hippo pathway activation has been shown to protect against neuronal death [ 92 , 93 , 96 ]. Increased LATS1 activation is found in cortical neurons of MCI and AD patients, while decreased YAP levels are observed in temporal and occipital tip tissues from AD patients [ 94 ].…”

Section: Functional Consequences Of Ad-induced Downregulation Of Willin/frmd6mentioning

confidence: 99%

Willin/FRMD6: A Multi-Functional Neuronal Protein Associated with Alzheimer’s Disease

Chen

Aitken

et al. 2021

Cells

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The FERM domain-containing protein 6 (FRMD6), also known as Willin, is an upstream regulator of Hippo signaling that has recently been shown to modulate actin cytoskeleton dynamics and mechanical phenotype of neuronal cells through ERK signaling. Physiological functions of Willin/FRMD6 in the nervous system include neuronal differentiation, myelination, nerve injury repair, and vesicle exocytosis. The newly established neuronal role of Willin/FRMD6 is of particular interest given the mounting evidence suggesting a role for Willin/FRMD6 in Alzheimer’s disease (AD), including a series of genome wide association studies that position Willin/FRMD6 as a novel AD risk gene. Here we describe recent findings regarding the role of Willin/FRMD6 in the nervous system and its actions in cellular perturbations related to the pathogenesis of AD.

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“…Along with the influence of patient age, central and peripheral sources of immune cells prominently contribute to secondary neurodegeneration during both the acute and chronic phases following stroke and TBI. [92][93][94][95][96][97] Indeed, neuroinflammation stands as the common denominator that accompanies both disease pathologies and closely parallels secondary neural cell loss throughout their progression. As such, elucidating the dynamic involvement of both central and peripheral sources, especially the interplay between the brain and the spleen, is key to understanding the mechanisms underlying neuroinflammation.…”

Section: Con Clus Ionmentioning

confidence: 99%

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

et al. 2020

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Acquired brain injury (ABI) entails any injury that disrupts neuronal activity and is not degenerative, hereditary, congenital, or induced by birth trauma. Traditional examples of ABI include not only stroke and traumatic brain injury (TBI), but also near drowning, aneurysm, tumor, meningitis and other infections involving the brain, and injuries resulting from lack of oxygen supply to the brain, such as those seen in myocardial infarction. ABI may involve a structural insult, changes to metabolic activity, or disruption to neuronal capabilities.While progressive loss of brain cells and debilitating motor and cognitive deficits play a role in all these disorders, stroke and TBI overlap particularly closely in pathology and impose an immense burden on the American and global populations. AbstractIschemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long-term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM-MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM-MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell-based combination treatments. K E Y W O R D Sbone marrow-derived mesenchymal stem cells, clinical trials, inflammation, ischemic stroke, preclinical studies, traumatic brain injury

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Inhibition of Lats1/p‐YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury

Abstract: Our work demonstrates that inhibition of Lats1/p-YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of TBI.

Cited by 18 publications

References 33 publications

Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury

Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury

Willin/FRMD6: A Multi-Functional Neuronal Protein Associated with Alzheimer’s Disease

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

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