Δ9-tetrahydrocannabinol and 2-AG decreases neurite outgrowth and differentially affects ERK1/2 and Akt signaling in hiPSC-derived cortical neurons

Shum, Carole; Dutan, Lucia; Annuario, Emily; Warre-Cornish, Katherine; Taylor, Samuel E.; Taylor, Roger; Andreae, Laura C.; Buckley, Noel J.; Price, John; Bhattacharyya, Sagnik; Srivastava, Deepak P.

doi:10.1016/j.mcn.2019.103463

Cited by 29 publications

(32 citation statements)

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“…To investigate this, we used hiPSC-NPCs from three typically developing male individuals with no history of psychiatric illness [M1, M2, and M3; table S1 and fig. S1; ( 27 , 28 )] and treated these cells with IFN-γ (25 ng/ml) daily on days (D) 17 to 21 of differentiation. Subsequently, IFN-γ was excluded from cell culture media, and neuronal differentiation was continued, resulting in post-mitotic hiPSC neurons ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Two ASD lines were generated using CytoTune Sendai reprogramming kits (Thermo Fisher Scientific, A16517). HiPSC reprogramming was validated as previously described ( 24 , 27 , 28 , 56 ). Briefly, genome-wide expression profiling using Illumina BeadChip v4 and the bioinformatics tool “Pluritest” was used to confirm hiPSC identity.…”

Section: Methodsmentioning

confidence: 99%

“…HiPSCs were differentiated as previously reported ( 24 ). HiPSCs were grown until 95 to 100% confluent and then neuralized using a modified dual SMAD inhibition protocol ( 24 , 27 , 28 , 56 ). For neuralization, StemFlex was replaced with a 1:1 mixture of N2- and B27-supplemented medium, made following the manufacturer’s guidelines (Thermo Fisher Scientific, 17502048 and 17504044) to which SMAD and Wnt inhibitors (10 μM SB431542, 1 μM dorsomorphin, and 2 μM XAV939) were added (hereafter known as N2:B27+++).…”

Section: Methodsmentioning

confidence: 99%

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Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

et al. 2020

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Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-γ (IFN-γ), in offspring’s brains play a central role. IFN-γ activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFN-γ is implicated in brain development. We tested the hypothesis that IFN-γ signaling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. Transient IFN-γ treatment of neural progenitors derived from human induced pluripotent stem cells increased neurite outgrowth. RNA sequencing analysis revealed that major histocompatibility complex class I (MHCI) genes were persistently up-regulated through neuronal differentiation—an effect that was mediated by IFN-γ-induced promyelocytic leukemia protein (PML) nuclear bodies. Critically, IFN-γ-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFN-γ disproportionately altered the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data implicate IFN-γ signaling in neurodevelopmental disorder etiology.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

et al. 2020

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“…These results provide a mechanism where FAK and MAPK integrate signals from CB 1 , integrins, and RTKs. CB 1 signaling through FAK and MAPK may play important physiological roles in CB 1 regulation of the actin cytoskeleton, neuronal migration, proliferation, and generation of neuritic processes (Harkany et al, 2008;Zorina et al, 2010;Jung et al, 2011;Peng and Guan, 2011;Gaffuri et al, 2012;Roskoski, 2012;Shum et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Studies have shown that CB 1 regulates ERK1/2 phosphorylation/activation via several mechanisms that include G i/o protein activation (Galve-Roperh et al, 2002;Davis et al, 2003;Dalton and Howlett, 2012), RTK transactivation (Dalton and Howlett, 2012), and Src activation (Derkinderen et al, 2003;Dalton and Howlett, 2012) under various stimuli and conditions. Given the importance of FAK and ERK1/2 in the endocannabinoid system's role in neuronal migration and neuritogenesis, it is important to determine whether CB 1 -mediated FAK 925 Tyr-P is required for efficient ERK1/2 pathway activation in neuronal focal adhesions (Cox et al, 2006;Harkany et al, 2008;Samuels et al, 2009;Zorina et al, 2010;Shum et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions

Dalton

Carney

Marshburn

et al. 2020

Front. Cell. Neurosci.

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CB 1 cannabinoid receptors (CB 1) are abundantly expressed in the nervous system where they regulate focal adhesion kinase (FAK) and the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1 and 2 (ERK1/2). However, the role of CB 1-stimulated FAK 925 tyrosine phosphorylation (Tyr-P) in regulating ERK1/2 activation remains undefined. Here, immunoblotting analyses using antibodies against FAK phospho-Tyr 925 and ERK2 phospho-Tyr 204 demonstrated CB 1-stimulated FAK 925 Tyr-P and ERK2 204 Tyr-P (0-5 min) which was followed by a decline in Tyr-P (5-20 min). CB 1 stimulated FAK-Grb2 association and Ras-mediated ERK2 activation. The FAK inhibitors Y11 and PF 573228 abolished FAK 925 Tyr-P and partially inhibited ERK2 204 Tyr-P. FAK 925 Tyr-P and ERK2 204 Tyr-P were adhesion-dependent, required an intact actin cytoskeleton, and were mediated by integrins, Flk-1 vascular endothelial growth factor receptors, and epidermal growth factor receptors. FAK 925 Tyr-P and ERK2 204 Tyr-P were blocked by the Gβγ inhibitor gallein, a GRK2 inhibitor, and GRK2 siRNA silencing, suggesting Gβγ and GRK2 participate in FAK-mediated ERK2 activation. Together, these studies indicate FAK 925 Tyr-P occurs concurrently with CB 1-stimulated ERK2 activation and requires the actin cytoskeleton and G i/o βγ-GRK2mediated cross-talk between CB 1 , integrins, and receptor tyrosine kinases (RTKs).

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The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death

Bockmann

Brito²,

Fragel-Madeira³

et al. 2022

Cell Mol Neurobiol

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The active principles of Cannabis sativa are potential treatments for several diseases, such as pain, seizures and anorexia. With the increase in the use of cannabis for medicinal purposes, a more careful assessment of the possible impacts on embryonic development becomes necessary. Surveys indicate that approximately 3.9% of pregnant women use cannabis in a recreational and/or medicinal manner. However, although the literature has already described the presence of endocannabinoid system components since the early stages of CNS development, many of their physiological effects during this stage have not yet been established. Moreover, it is still uncertain how the endocannabinoid system can be altered in terms of cell proliferation and cell fate, neural migration, neural differentiation, synaptogenesis and particularly cell death. In relation to cell death in the CNS, knowledge about the effects of cannabinoids is scarce. Thus, the present work aims to review the role of the endocannabinoid system in different aspects of CNS development and discuss possible side effects or even opportunities for treating some conditions in the development of this tissue.

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Δ9-tetrahydrocannabinol and 2-AG decreases neurite outgrowth and differentially affects ERK1/2 and Akt signaling in hiPSC-derived cortical neurons

Abstract: 9 -tetrahydrocannabinol and 2-AG decreases neurite outgrowth and differentially affects ERK1/2 and Akt signaling in hiPSC-derived cortical neurons. Molecular and Cellular Neuroscience, 103, [103463].

Cited by 29 publications

References 53 publications

Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

CB1 Cannabinoid Receptors Stimulate Gβγ-GRK2-Mediated FAK Phosphorylation at Tyrosine 925 to Regulate ERK Activation Involving Neuronal Focal Adhesions

The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death

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