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A meckelin-filamin A interaction mediates ciliogenesis

A meckelin-filamin A interaction mediates ciliogenesis
A meckelin-filamin A interaction mediates ciliogenesis
MKS3, encoding the transmembrane receptor meckelin, is mutated in Meckel-Gruber syndrome (MKS), an autosomal-recessive ciliopathy. Meckelin localizes to the primary cilium, basal body and elsewhere within the cell. Here, we found that the cytoplasmic domain of meckelin directly interacts with the actin-binding protein filamin A, potentially at the apical cell surface associated with the basal body. Mutations in FLNA, the gene for filamin A, cause periventricular heterotopias. We identified a single consanguineous patient with an MKS-like ciliopathy that presented with both MKS and cerebellar heterotopia, caused by an unusual in-frame deletion mutation in the meckelin C-terminus at the region of interaction with filamin A. We modelled this mutation and found it to abrogate the meckelin-filamin A interaction. Furthermore, we found that loss of filamin A by siRNA knockdown, in patient cells, and in tissues from Flna(Dilp2) null mouse embryos results in cellular phenotypes identical to those caused by meckelin loss, namely basal body positioning and ciliogenesis defects. In addition, morpholino knockdown of flna in zebrafish embryos significantly increases the frequency of dysmorphology and severity of ciliopathy developmental defects caused by mks3 knockdown. Our results suggest that meckelin forms a functional complex with filamin A that is disrupted in MKS and causes defects in neuronal migration and Wnt signalling. Furthermore, filamin A has a crucial role in the normal processes of ciliogenesis and basal body positioning. Concurrent with these processes, the meckelin-filamin A signalling axis may be a key regulator in maintaining correct, normal levels of Wnt signalling.
0964-6906
1272-1286
Adams, M.
aa223819-70bb-4104-b396-0c2d24c861fd
Simms, R.J.
cd0eafc8-6c5e-402c-ac2e-eb8fd59a4ab7
Abdelhamed, Z.
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Dawe, H.R.
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Szymanska, K.
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Logan, C.V.
b63a9c90-75ff-409a-94da-c3d8581fa028
Wheway, G.
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Pitt, E.
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Gull, K.
e206b1bc-9d99-4bae-89a6-218a27511d16
Knowles, M.A.
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Blair, E.
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Cross, S.H.
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Sayer, J.A.
1496c7ee-9f80-4121-a6aa-bebd336b26a9
Johnson, C.A.
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Adams, M.
aa223819-70bb-4104-b396-0c2d24c861fd
Simms, R.J.
cd0eafc8-6c5e-402c-ac2e-eb8fd59a4ab7
Abdelhamed, Z.
b4ff1341-981a-4c9b-8e4a-f7ae4e5d7c9d
Dawe, H.R.
9d11f61e-2b2f-4018-94f3-8d560b59cbed
Szymanska, K.
62e8f902-4ec6-49e1-af6f-0f3fccbfdf4e
Logan, C.V.
b63a9c90-75ff-409a-94da-c3d8581fa028
Wheway, G.
2e547e5d-b921-4243-a071-2208fd4cc090
Pitt, E.
b0875a15-8108-4444-baab-a327bd0a2417
Gull, K.
e206b1bc-9d99-4bae-89a6-218a27511d16
Knowles, M.A.
3e210668-15cf-4a81-8f76-e2135e72feea
Blair, E.
ec4fb4c4-a134-4bf2-a4aa-328de5f0c798
Cross, S.H.
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Sayer, J.A.
1496c7ee-9f80-4121-a6aa-bebd336b26a9
Johnson, C.A.
6673df13-c2a2-4e82-84a6-69d571dea103

Adams, M., Simms, R.J., Abdelhamed, Z., Dawe, H.R., Szymanska, K., Logan, C.V., Wheway, G., Pitt, E., Gull, K., Knowles, M.A., Blair, E., Cross, S.H., Sayer, J.A. and Johnson, C.A. (2012) A meckelin-filamin A interaction mediates ciliogenesis. Human Molecular Genetics, 21 (6), 1272-1286. (doi:10.1093/hmg/ddr557).

Record type: Article

Abstract

MKS3, encoding the transmembrane receptor meckelin, is mutated in Meckel-Gruber syndrome (MKS), an autosomal-recessive ciliopathy. Meckelin localizes to the primary cilium, basal body and elsewhere within the cell. Here, we found that the cytoplasmic domain of meckelin directly interacts with the actin-binding protein filamin A, potentially at the apical cell surface associated with the basal body. Mutations in FLNA, the gene for filamin A, cause periventricular heterotopias. We identified a single consanguineous patient with an MKS-like ciliopathy that presented with both MKS and cerebellar heterotopia, caused by an unusual in-frame deletion mutation in the meckelin C-terminus at the region of interaction with filamin A. We modelled this mutation and found it to abrogate the meckelin-filamin A interaction. Furthermore, we found that loss of filamin A by siRNA knockdown, in patient cells, and in tissues from Flna(Dilp2) null mouse embryos results in cellular phenotypes identical to those caused by meckelin loss, namely basal body positioning and ciliogenesis defects. In addition, morpholino knockdown of flna in zebrafish embryos significantly increases the frequency of dysmorphology and severity of ciliopathy developmental defects caused by mks3 knockdown. Our results suggest that meckelin forms a functional complex with filamin A that is disrupted in MKS and causes defects in neuronal migration and Wnt signalling. Furthermore, filamin A has a crucial role in the normal processes of ciliogenesis and basal body positioning. Concurrent with these processes, the meckelin-filamin A signalling axis may be a key regulator in maintaining correct, normal levels of Wnt signalling.

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More information

Accepted/In Press date: 22 November 2011
e-pub ahead of print date: 25 November 2011
Published date: 15 March 2012

Identifiers

Local EPrints ID: 423524
URI: https://eprints.soton.ac.uk/id/eprint/423524
ISSN: 0964-6906
PURE UUID: 710870bf-81a8-440b-8059-ac2eab833397
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: 14 Mar 2019 01:21

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Contributors

Author: M. Adams
Author: R.J. Simms
Author: Z. Abdelhamed
Author: H.R. Dawe
Author: K. Szymanska
Author: C.V. Logan
Author: G. Wheway ORCID iD
Author: E. Pitt
Author: K. Gull
Author: M.A. Knowles
Author: E. Blair
Author: S.H. Cross
Author: J.A. Sayer
Author: C.A. Johnson

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