Early But Not Delayed Optogenetic RAF Activation Promotes Astrocytogenesis in Mouse Neural Progenitors

Su, Yixun; Huang, Xiaomin; Huang, Zhongwen; Huang, Taida; Li, Tao; Fan, Huaxun; Zhang, Kai; Yi, Chenju

doi:10.1016/j.jmb.2020.06.020

Cited by 8 publications

(6 citation statements)

References 29 publications

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“…Opsin-free optogenetics allows light-mediated modulation of the intracellular signalling pathways in live cells with high temporal and spatial accuracy. 42 , 56–59 Here, we used an in-house developed optogenetic tool (OptoLRP6). 40 As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

Wang

Huang

et al. 2022

Brain

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Alzheimer’s disease (AD) is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for AD pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD. Here, we showed dysfunctional BBB in AD patients reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells (BECs). In the APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and Aβ-treated BECs, we found suppressed Wnt/β-catenin signaling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signaling) to activate Wnt/β-catenin pathway, BBB malfunction was restored by preventing Aβ-induced BEC impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate BBB malfunction induced by Aβ, which may be a potential treatment strategy for AD.

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Section: Resultsmentioning

confidence: 99%

Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

Wang

Huang

et al. 2022

Brain

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“…RAF1 encodes protein named MAP kinase kinase kinase (MAP3K), playing an intermediate regulatory role in the linear RAS/RAF/MEK/ERK pathway ( Ghousein et al, 2020 ). It was reported that RAF1 was involved in promoting neuronal neurite growth ( Su et al, 2020 ). Moreover, RAF1 activation mediates cell death and survival, oncogenic transformation and hematopoietic function.…”

Section: Discussionmentioning

confidence: 99%

Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer’s disease

Deng

Feng²,

Lv³

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a complex, and multifactorial neurodegenerative disease. Previous studies have revealed that oxidative stress, synaptic toxicity, autophagy, and neuroinflammation play crucial roles in the progress of AD, however, its pathogenesis is still unclear. Recent researches have indicated that ferroptosis, an iron-dependent programmed cell death, might be involved in the pathogenesis of AD. Therefore, we aim to screen correlative ferroptosis-related genes (FRGs) in the progress of AD to clarify insights into the diagnostic value. Interestingly, we identified eight FRGs were significantly differentially expressed in AD patients. 10,044 differentially expressed genes (DEGs) were finally identified by differential expression analysis. The following step was investigating the function of DEGs using gene set enrichment analysis (GSEA). Weight gene correlation analysis was performed to explore ten modules and 104 hub genes. Subsequently, based on machine learning algorithms, we constructed diagnostic classifiers to select characteristic genes. Through the multivariable logistic regression analysis, five features (RAF1, NFKBIA, MOV10L1, IQGAP1, FOXO1) were then validated, which composed a diagnostic model of AD. Thus, our findings not only developed genetic diagnostics strategy, but set a direction for further study of the disease pathogenesis and therapy targets.

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“…Following similar approaches, Cry2-based optogenetic toolkits for additional signaling cascades have also been recently reported, including optoRaf (Su et al, 2020 ), optoRhoA (Bugaj et al, 2013 ), optoCdc42 (Bugaj et al, 2013 ), optoEphB2 (Locke et al, 2017 ), and light sensitive myosin motors (Zhang et al, 2021 ). Overall, these newly developed optogenetic toolkits enable the spatiotemporal profiling of signal activation in vitro and enable applications in understanding the signaling dynamics underlying key neurotrophin cascades and cellular function in the nervous system.…”

Section: Optogenetics In Cellular Function and Synaptic Communicationmentioning

confidence: 99%

Optogenetic Application to Investigating Cell Behavior and Neurological Disease

Zhu

Johnson

Schaffer

2022

Front. Cell. Neurosci.

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Cells reside in a dynamic microenvironment that presents them with regulatory signals that vary in time, space, and amplitude. The cell, in turn, interprets these signals and accordingly initiates downstream processes including cell proliferation, differentiation, migration, and self-organization. Conventional approaches to perturb and investigate signaling pathways (e.g., agonist/antagonist addition, overexpression, silencing, knockouts) are often binary perturbations that do not offer precise control over signaling levels, and/or provide limited spatial or temporal control. In contrast, optogenetics leverages light-sensitive proteins to control cellular signaling dynamics and target gene expression and, by virtue of precise hardware control over illumination, offers the capacity to interrogate how spatiotemporally varying signals modulate gene regulatory networks and cellular behaviors. Recent studies have employed various optogenetic systems in stem cell, embryonic, and somatic cell patterning studies, which have addressed fundamental questions of how cell-cell communication, subcellular protein localization, and signal integration affect cell fate. Other efforts have explored how alteration of signaling dynamics may contribute to neurological diseases and have in the process created physiologically relevant models that could inform new therapeutic strategies. In this review, we focus on emerging applications within the expanding field of optogenetics to study gene regulation, cell signaling, neurodevelopment, and neurological disorders, and we comment on current limitations and future directions for the growth of the field.

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Early But Not Delayed Optogenetic RAF Activation Promotes Astrocytogenesis in Mouse Neural Progenitors

Cited by 8 publications

References 29 publications

Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer’s disease

Optogenetic Application to Investigating Cell Behavior and Neurological Disease

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