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Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton

Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton
Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton
Meckel-Gruber syndrome (MKS) is a severe autosomal recessively inherited disorder caused by mutations in genes that encode components of the primary cilium and basal body. Here we show that two MKS proteins, MKS1 and meckelin, that are required for centrosome migration and ciliogenesis interact with actin-binding isoforms of nesprin-2 (nuclear envelope spectrin repeat protein 2, also known as Syne-2 and NUANCE). Nesprins are important scaffold proteins for maintenance of the actin cytoskeleton, nuclear positioning and nuclear-envelope architecture. However, in ciliated-cell models, meckelin and nesprin-2 isoforms colocalized at filopodia prior to the establishment of cell polarity and ciliogenesis. Loss of nesprin-2 and nesprin-1 shows that both mediate centrosome migration and are then essential for ciliogenesis, but do not otherwise affect apical-basal polarity. Loss of meckelin (by siRNA and in a patient cell-line) caused a dramatic remodelling of the actin cytoskeleton, aberrant localization of nesprin-2 isoforms to actin stress-fibres and activation of RhoA signalling. These findings further highlight the important roles of the nesprins during cellular and developmental processes, particularly in general organelle positioning, and suggest that a mechanistic link between centrosome positioning, cell polarity and the actin cytoskeleton is required for centrosomal migration and is essential for early ciliogenesis.
0021-9533
2716-2726
Dawe, H.R.
665b383c-51a9-4a73-b871-f236fb7a11c2
Adams, M.
65b1f41e-7a98-4159-b46c-309b5a8fbdd5
Wheway, G.
2e547e5d-b921-4243-a071-2208fd4cc090
Szymanska, K.
c2757637-5dba-453e-9fc6-718089332294
Logan, C.V.
0708afb9-069b-47f9-8b59-d767b6d2e256
Noegel, A.A.
c25414f2-da3a-48b5-8ccc-2baf51f73edb
Gull, K.
0d08fa94-0705-4804-b0ea-726fa0ad25fa
Johnson, C.A.
eeba2797-8db7-444c-a430-41bca8d46742
Dawe, H.R.
665b383c-51a9-4a73-b871-f236fb7a11c2
Adams, M.
65b1f41e-7a98-4159-b46c-309b5a8fbdd5
Wheway, G.
2e547e5d-b921-4243-a071-2208fd4cc090
Szymanska, K.
c2757637-5dba-453e-9fc6-718089332294
Logan, C.V.
0708afb9-069b-47f9-8b59-d767b6d2e256
Noegel, A.A.
c25414f2-da3a-48b5-8ccc-2baf51f73edb
Gull, K.
0d08fa94-0705-4804-b0ea-726fa0ad25fa
Johnson, C.A.
eeba2797-8db7-444c-a430-41bca8d46742

Dawe, H.R., Adams, M., Wheway, G., Szymanska, K., Logan, C.V., Noegel, A.A., Gull, K. and Johnson, C.A. (2009) Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton. Journal of Cell Science, 122 (15), 2716-2726. (doi:10.1242/jcs.043794).

Record type: Article

Abstract

Meckel-Gruber syndrome (MKS) is a severe autosomal recessively inherited disorder caused by mutations in genes that encode components of the primary cilium and basal body. Here we show that two MKS proteins, MKS1 and meckelin, that are required for centrosome migration and ciliogenesis interact with actin-binding isoforms of nesprin-2 (nuclear envelope spectrin repeat protein 2, also known as Syne-2 and NUANCE). Nesprins are important scaffold proteins for maintenance of the actin cytoskeleton, nuclear positioning and nuclear-envelope architecture. However, in ciliated-cell models, meckelin and nesprin-2 isoforms colocalized at filopodia prior to the establishment of cell polarity and ciliogenesis. Loss of nesprin-2 and nesprin-1 shows that both mediate centrosome migration and are then essential for ciliogenesis, but do not otherwise affect apical-basal polarity. Loss of meckelin (by siRNA and in a patient cell-line) caused a dramatic remodelling of the actin cytoskeleton, aberrant localization of nesprin-2 isoforms to actin stress-fibres and activation of RhoA signalling. These findings further highlight the important roles of the nesprins during cellular and developmental processes, particularly in general organelle positioning, and suggest that a mechanistic link between centrosome positioning, cell polarity and the actin cytoskeleton is required for centrosomal migration and is essential for early ciliogenesis.

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More information

Accepted/In Press date: 5 May 2009
e-pub ahead of print date: 13 July 2009
Published date: 22 July 2009

Identifiers

Local EPrints ID: 423525
URI: https://eprints.soton.ac.uk/id/eprint/423525
ISSN: 0021-9533
PURE UUID: dd7ad3e1-4111-42b0-b3ac-e509718bb0e8
ORCID for G. Wheway: ORCID iD orcid.org/0000-0002-0494-0783

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Date deposited: 25 Sep 2018 16:30
Last modified: 26 Nov 2019 01:22

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Contributors

Author: H.R. Dawe
Author: M. Adams
Author: G. Wheway ORCID iD
Author: K. Szymanska
Author: C.V. Logan
Author: A.A. Noegel
Author: K. Gull
Author: C.A. Johnson

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