Defective INPP5E distribution in NPHP1‐related Senior–Loken syndrome

Ning, Ke; Song, Emilie; Sendayen, Brent E.; Prosseda, Philipp P.; Chang, Kun-Che; Ghaffarieh, Alireza; Alvarado, Jorge A.; Wang, Biao; Haider, Kathryn M.; Berbari, Nicolas F.; Hu, Yang; Sun, Yang

doi:10.1002/mgg3.1566

Cited by 14 publications

(18 citation statements)

References 39 publications

(52 reference statements)

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“…1,2 In many cell types, primary cilia can function as a cellular antenna to sense external cues and transduce intracellular signaling involved in diverse cellular processes during development. 1,[3][4][5][6] Essential to central nervous system development, primary cilia are required for tissue patterning, neuronal migration, learning, and memory formation. [7][8][9][10] Defects of cilia in humans can result in a group of conditions called ciliopathies, that present in the brain, kidneys, and eyes.…”

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confidence: 99%

Primary Cilia in Amacrine Cells in Retinal Development

Ning

Sendayen

Kowal

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Primary cilia are conserved organelles found in polarized cells within the eye that regulate cell growth, migration, and differentiation. Although the role of cilia in photoreceptors is well-studied, the formation of cilia in other retinal cell types has received little attention. In this study, we examined the ciliary profile focused on the inner nuclear layer of retinas in mice and rhesus macaque primates. METHODS.Retinal sections or flatmounts from Arl13b-Cetn2 tg transgenic mice were immunostained for cell markers (Pax6, Sox9, Chx10, Calbindin, Calretinin, ChaT, GAD67, Prox1, TH, and vGluT3) and analyzed by confocal microscopy. Primate retinal sections were immunostained for ciliary and cell markers (Pax6 and Arl13b). Optical coherence tomography (OCT) and ERGs were used to assess visual function of Vift88 mice. RESULTS.During different stages of mouse postnatal eye development, we found that cilia are present in Pax6-positive amacrine cells, which were also observed in primate retinas. The cilia of subtypes of amacrine cells in mice were shown by immunostaining and electron microscopy. We also removed primary cilia from vGluT3 amacrine cells in mouse and found no significant vision defects. In addition, cilia were present in the outer limiting membrane, suggesting that a population of Müller glial cells forms cilia. CONCLUSIONS.We report that several subpopulations of amacrine cells in inner nuclear layers of the retina form cilia during early retinal development in mice and primates.

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confidence: 99%

Primary Cilia in Amacrine Cells in Retinal Development

Ning

Sendayen

Kowal

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…Evidence from zebrafish ( 64 ) and mice ( 36 , 48 ) shows that the BBSome interacts with the TZ and has overlapping roles in regulating primary ciliogenesis ( 65 ). A study in human renal tubular cells shows that INPP5E was absent from primary cilia with a dysfunctional TZ ( 66 ). Importantly, deletion of BBS4 in mouse embryonic fibroblasts also results in a significantly reduced ciliary localization of INPP5E ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies

Xie¹,

Habif²,

Ukhanov³

et al. 2022

JCI Insight

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Ciliopathies are a class of genetic diseases resulting in cilia dysfunction in multiple organ systems, including the olfactory system. Currently, there are no available curative treatments for olfactory dysfunction and other symptoms in ciliopathies. The loss or shortening of olfactory cilia, as seen in multiple mouse models of the ciliopathy Bardet-Biedl syndrome (BBS), results in olfactory dysfunction. However, the underlying mechanism of the olfactory cilia reduction is unknown, thus limiting the development of therapeutic approaches for BBS and other ciliopathies. Here, we demonstrated that PI(4,5)P2, a phosphoinositide typically excluded from olfactory cilia, aberrantly redistributed into the residual cilia of BBS mouse models, which caused F-actin ciliary infiltration.Importantly, PI(4,5)P2 and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P2 by overexpression of INPP5E restored cilia length, and rescued odor detection and odor perception in BBS. Together, our data indicate that PI(4,5)P2 and F-actin-dependent cilia disassembly is a common mechanism contributing to the loss of olfactory cilia in BBS and provide valuable pan therapeutic intervention targets for the treatment of ciliopathies.

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“…Although mutations in other JBTS genes are known to disrupt INPP5E ciliary localization, mutations in INPP5E itself had not been reported to do so 3,5,[13][14][15][16][17][18][19][20] . Instead, INPP5E mutations were shown to impair INPP5E enzyme activity, without affecting ciliary targeting 8,29 .…”

Section: Multiple Clss Target Inpp5e To Ciliamentioning

confidence: 99%

“…More specifically, JBTS-causative genes regulate a ciliary signaling network, one of whose main nodes is the ciliary phosphoinositide phosphatase INPP5E (Inositol polyphosphate-5-phosphatase E, formerly known as Pharbin, or as type IV 72 kDa 5-phosphatase) [7][8][9][10][11] . Evidence for the central role of INPP5E in JBTS includes: (i) INPP5E is one of the most commonly mutated JBTS genes 6 ; (ii) mouse models of INPP5E loss of function recapitulate key features of human JBTS, including the axon tract defects leading to MTS in humans 7,12 ; (iii) most other JBTS genes encode proteins required for INPP5E ciliary targeting 3,5,[13][14][15][16][17][18][19][20] ; and (iv) the few JBTS genes that may not be needed for INPP5E ciliary targeting regulate the same pathways as INPP5E, like Hedgehog (Hh) signaling or ciliary stability [21][22][23][24][25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting

Cilleros-Rodríguez

Martin-Morales

Barbeito

et al. 2022

Preprint

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Primary cilia are sensory membrane protrusions whose dysfunction causes diseases named ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, such as cilium stability, trafficking, signaling, or exovesicle release. Despite its key ciliary roles, how INPP5E accumulates in cilia remains poorly understood. Herein, we show that INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four ciliary localization signals (CLSs), the first two of which we newly discover: LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial redundancy between CLS1 and CLS4 explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 on the catalytic domain surface clarifies why CLS3 and CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations in INPP5E catalytic domain affect its ciliary targeting, and shed light on the mechanisms of action of each CLS. Thus, we find that CLS2 and CLS3 promote interaction with TULP3 and ARL13B, while downregulating CEP164 binding. On the other hand, CLS4 recruits PDE6D, RPGR and ARL13B, and cooperates with CLS1 in ATG16L1 binding. Lastly, we show INPP5E immune synapse targeting is CLS-independent. Altogether, we reveal unusual complexity in INPP5E ciliary targeting mechanisms, likely reflecting its multiple key roles in ciliary biology.

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Defective INPP5E distribution in NPHP1‐related Senior–Loken syndrome

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 14 publications

References 39 publications

Primary Cilia in Amacrine Cells in Retinal Development

Primary Cilia in Amacrine Cells in Retinal Development

Reversal of ciliary mechanisms of disassembly rescues olfactory dysfunction in ciliopathies

Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting

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