Optogenetic Control of the Canonical Wnt Signaling Pathway During Xenopus laevis Embryonic Development

Krishnamurthy, Vishnu V.; Hwang, Hyo-Jeong; Fu, Jia; Yang, Jing; Zhang, Kai

doi:10.1016/j.jmb.2021.167050

Cited by 6 publications

(6 citation statements)

References 39 publications

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“… 42 , 56–59 Here, we used an in-house developed optogenetic tool (OptoLRP6). 40 As shown in Fig. 5A , under blue-light stimulation, the CRY2-CIBN association allows the interaction between LRP6 and transmembrane protein 198 (TMEM198) to specifically activate LRP6-Wnt signalling.…”

Section: Resultsmentioning

confidence: 98%

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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: 98%

“…The plasmid vector was constructed as described previously. 40 The lentivirus was produced using third-generation lentiviral generation systems, the virus envelope plasmid, packaging plasmids and OptoLRP6, ΔCRY2 plasmids were transfected into 293T cell lines. Eight hours after transfection, the media were refreshed.…”

Section: Methodsmentioning

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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“…Finally, optogenetics can function as a precision perturbation tool in developmental biology (Krueger et al, 2019). In vivo application include decoding signaling dynamics during Xenopus development, where light-mediated Raf/MEK/ERK activation, accomplished by membrane localization of Raf1 via CRY2-CIBN association, was demonstrated to induce a tail-like structure after germ layer formation (Krishnamurthy et al, 2016(Krishnamurthy et al, , 2017, and optoWnt activation results in axis duplication (Krishnamurthy et al, 2021).…”

Section: Optogenetics In Organismal Developmentmentioning

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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“…Under the dark condition, LRP6‐CRY2 is distributed in the cytosol and cannot initiate Wnt signaling. Light‐induced CRY2‐CIBN heterodimerization results in membrane recruitment of LRP6c and the subsequent activation of the Wnt pathway (Krishnamurthy et al, 2021).…”

Section: Applications Of Optogenetics In Developmental Biologymentioning

confidence: 99%

“…The authors demonstrated that ventral activation of the opto‐LRP6 during pre‐MBT stages creates an ectopic Spemann Organizer and induces dorsal axis formation. In contrast, dorsal activation of opto‐LRP6 from the late blastula to gastrula stages leads to severely posteriorized embryos that lack heads (Krishnamurthy et al, 2021).…”

Section: Applications Of Optogenetics In Developmental Biologymentioning

confidence: 99%

Precise modulation of embryonic development through optogenetics

Fan

Barnes

Hwang

et al. 2022

Genesis

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Summary The past decade has witnessed enormous progress in optogenetics, which uses photo‐sensitive proteins to control signal transduction in live cells and animals. The ever‐increasing amount of optogenetic tools, however, could overwhelm the selection of appropriate optogenetic strategies. In this work, we summarize recent progress in this emerging field and highlight the application of opsin‐free optogenetics in studying embryonic development, focusing on new insights gained into optical induction of morphogenesis, cell polarity, cell fate determination, tissue differentiation, neuronal regeneration, synaptic plasticity, and removal of cells during development.

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Optogenetic Control of the Canonical Wnt Signaling Pathway During Xenopus laevis Embryonic Development

Cited by 6 publications

References 39 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

Optogenetic Application to Investigating Cell Behavior and Neurological Disease

Precise modulation of embryonic development through optogenetics

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