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Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis

Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis
Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis
To investigate the contribution of ion channels to ciliogenesis, we carried out a small interfering RNA (siRNA)-based reverse genetics screen of all ion channels in the mouse genome in murine inner medullary collecting duct kidney cells. This screen revealed four candidate ion channel genes: Kcnq1, Kcnj10, Kcnf1 and Clcn4. We show that these four ion channels localize to renal tubules, specifically to the base of primary cilia. We report that human KCNQ1 Long QT syndrome disease alleles regulate renal ciliogenesis; KCNQ1-p.R518X, -p.A178T and -p.K362R could not rescue ciliogenesis after Kcnq1-siRNA-mediated depletion in contrast to wild-type KCNQ1 and benign KCNQ1-p.R518Q, suggesting that the ion channel function of KCNQ1 regulates ciliogenesis. In contrast, we demonstrate that the ion channel function of KCNJ10 is independent of its effect on ciliogenesis. Our data suggest that these four ion channels regulate renal ciliogenesis through the periciliary diffusion barrier or the ciliary pocket, with potential implication as genetic contributors to ciliopathy pathophysiology. The new functional roles of a subset of ion channels provide new insights into the disease pathogenesis of channelopathies, which might suggest future therapeutic approaches.
0021-9533
4550-4559
Slaats, Gisela G.
23d0d509-bc29-403d-a658-75f42002be7a
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Foletto, Veronica
657bea43-d813-4139-87c4-bcece2d089f6
Szymanska, Katarzyna
64504af9-0b59-47b4-b2e9-db50464d3e3f
van Balkom, Bas W.M.
1d22810b-1fb0-4ee5-b44f-db219452c331
Logister, Ive
61a18296-0685-49aa-aa07-a1f582b4814c
Den Ouden, Krista
d54abf53-e521-4d5f-826b-a413cf6141db
Keijzer-Veen, Mandy G.
7895433f-85d4-4bb1-ac99-1791d42f15dd
Lilien, Marc R.
c73befd2-cc64-484d-a19c-91a400491a65
Knoers, Nine V.
9846bf53-bd05-47da-b578-09dfc7534513
Johnson, Colin A.
eeba2797-8db7-444c-a430-41bca8d46742
Giles, Rachel H.
bd549bac-2cb3-4209-8373-e12ba63c2f17
Slaats, Gisela G.
23d0d509-bc29-403d-a658-75f42002be7a
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Foletto, Veronica
657bea43-d813-4139-87c4-bcece2d089f6
Szymanska, Katarzyna
64504af9-0b59-47b4-b2e9-db50464d3e3f
van Balkom, Bas W.M.
1d22810b-1fb0-4ee5-b44f-db219452c331
Logister, Ive
61a18296-0685-49aa-aa07-a1f582b4814c
Den Ouden, Krista
d54abf53-e521-4d5f-826b-a413cf6141db
Keijzer-Veen, Mandy G.
7895433f-85d4-4bb1-ac99-1791d42f15dd
Lilien, Marc R.
c73befd2-cc64-484d-a19c-91a400491a65
Knoers, Nine V.
9846bf53-bd05-47da-b578-09dfc7534513
Johnson, Colin A.
eeba2797-8db7-444c-a430-41bca8d46742
Giles, Rachel H.
bd549bac-2cb3-4209-8373-e12ba63c2f17

Slaats, Gisela G., Wheway, Gabrielle, Foletto, Veronica, Szymanska, Katarzyna, van Balkom, Bas W.M., Logister, Ive, Den Ouden, Krista, Keijzer-Veen, Mandy G., Lilien, Marc R., Knoers, Nine V., Johnson, Colin A. and Giles, Rachel H. (2015) Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis. Journal of Cell Science, 128 (24), 4550-4559. (doi:10.1242/jcs.176065).

Record type: Article

Abstract

To investigate the contribution of ion channels to ciliogenesis, we carried out a small interfering RNA (siRNA)-based reverse genetics screen of all ion channels in the mouse genome in murine inner medullary collecting duct kidney cells. This screen revealed four candidate ion channel genes: Kcnq1, Kcnj10, Kcnf1 and Clcn4. We show that these four ion channels localize to renal tubules, specifically to the base of primary cilia. We report that human KCNQ1 Long QT syndrome disease alleles regulate renal ciliogenesis; KCNQ1-p.R518X, -p.A178T and -p.K362R could not rescue ciliogenesis after Kcnq1-siRNA-mediated depletion in contrast to wild-type KCNQ1 and benign KCNQ1-p.R518Q, suggesting that the ion channel function of KCNQ1 regulates ciliogenesis. In contrast, we demonstrate that the ion channel function of KCNJ10 is independent of its effect on ciliogenesis. Our data suggest that these four ion channels regulate renal ciliogenesis through the periciliary diffusion barrier or the ciliary pocket, with potential implication as genetic contributors to ciliopathy pathophysiology. The new functional roles of a subset of ion channels provide new insights into the disease pathogenesis of channelopathies, which might suggest future therapeutic approaches.

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More information

Accepted/In Press date: 4 November 2015
e-pub ahead of print date: 6 November 2015
Published date: 15 December 2015

Identifiers

Local EPrints ID: 423511
URI: http://eprints.soton.ac.uk/id/eprint/423511
ISSN: 0021-9533
PURE UUID: 751d6246-cd4d-4bc8-82be-aaa61e76ee75
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783

Catalogue record

Date deposited: 25 Sep 2018 16:30
Last modified: 09 Jan 2022 04:05

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Contributors

Author: Gisela G. Slaats
Author: Veronica Foletto
Author: Katarzyna Szymanska
Author: Bas W.M. van Balkom
Author: Ive Logister
Author: Krista Den Ouden
Author: Mandy G. Keijzer-Veen
Author: Marc R. Lilien
Author: Nine V. Knoers
Author: Colin A. Johnson
Author: Rachel H. Giles

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