2020
DOI: 10.1126/sciadv.aay8699
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Optogenetic stimulation of phosphoinositides reveals a critical role of primary cilia in eye pressure regulation

Abstract: Glaucoma is a group of progressive optic neuropathies that cause irreversible vision loss. Although elevated intraocular pressure (IOP) is associated with the development and progression of glaucoma, the mechanisms for its regulation are not well understood. Here, we have designed CIBN/CRY2-based optogenetic constructs to study phosphoinositide regulation within distinct subcellular compartments. We show that stimulation of CRY2-OCRL, an inositol 5-phosphatase, increases aqueous humor outflow and lowers IOP in… Show more

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Cited by 21 publications
(30 citation statements)
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“…2 A and B). These results are in agreement with previous reports exploring the effects of TRPV4 activation in mouse eyes (15,44). To show the importance of TRPV4 channels in maintenance of normal IOP, we selectively deleted TRPV4 channel from mouse TM by intravitreally injecting Ad5-Cre in TRPV4 f/f mouse eyes.…”
Section: Discussionsupporting
confidence: 91%
See 1 more Smart Citation
“…2 A and B). These results are in agreement with previous reports exploring the effects of TRPV4 activation in mouse eyes (15,44). To show the importance of TRPV4 channels in maintenance of normal IOP, we selectively deleted TRPV4 channel from mouse TM by intravitreally injecting Ad5-Cre in TRPV4 f/f mouse eyes.…”
Section: Discussionsupporting
confidence: 91%
“…In the conventional outflow pathway, studies have demonstrated that TM cells respond to mechanical stressors like IOP elevation by altering their morphology (50,51). A recent study has shown that opening of mechanically activated TRPV4 channels in TM cells via GSK101 leads to Ca 2+ -mediated rearrangement of cytoskeletal actin filaments, which causes cellular contraction and an increase in AH drainage, presumably via the paracellular pathway (44). However, the temporal nature and magnitude of such cellular contractions that lead to increased AH drainage are yet to be determined.…”
Section: Physiologymentioning
confidence: 99%
“…To improve these limitations, optogenetic systems that use light as an external cue to control the behavior of microtubules have been developed. These systems are achieved by blue light–triggered dimerization of different partners including iLID/SSPB ( Adikes et al, 2018 ), Cry2/CIBN ( Prosseda et al, 2020 ), and LOV2/Zdk1 ( VanHaren et al, 2018 ; vanHaren et al, 2020 ). The crosslink between the microtubule plus end and F-actin that is triggered by the light temporally perturbs the microtubule dynamics in living cells ( Adikes et al, 2018 ).…”
Section: New Methods Enabling the Spatiotemporal Manipulation Of Axonmentioning
confidence: 99%
“…The cAMP level in primary cilia or flagella can be regulated by light-activated phosphodiesterase (LAPD), which therefore allows scientists to temporally manipulate sperm motility or to study the spatial aspect of cAMP signaling in primary cilia ( Raju et al, 2019 ; Hansen et al, 2020 ). In addition, with the Cry2/CIBN-based optogenetic method, scientists can spatiotemporally manipulate the level of phosphoinositide in primary cilia, which regulates eye pressure ( Prosseda et al, 2020 ). These optogenetic tools should also have applications with respect to spatiotemporally and reversibly manipulate tubulin PTMs under the control of light illumination.…”
Section: New Methods Enabling the Spatiotemporal Manipulation Of Axonmentioning
confidence: 99%
“…Somatostatin receptor 3 (SSTR3) ciliary targeting sequence was cloned into CIBN-EGFP as previously described. 46 Lipofectamine 3000 (Invitrogen) or polyethylenimine (Sigma, St Louis, MO) was used to transfect optogenetic constructs or subclone them separately into AAV2.…”
Section: Methodsmentioning
confidence: 99%