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Wdpcp, a PCP Protein Required for Ciliogenesis, Regulates Directional Cell Migration and Cell Polarity by Direct Modulation of the Actin Cytoskeleton

Cui, C and Chatterjee, B and Lozito, TP and Zhang, Z and Francis, RJ and Yagi, H and Swanhart, LM and Sanker, S and Francis, D and Yu, Q and San Agustin, JT and Puligilla, C and Chatterjee, T and Tansey, T and Liu, X and Kelley, MW and Spiliotis, ET and Kwiatkowski, AV and Tuan, R and Pazour, GJ and Hukriede, NA and Lo, CW (2013) Wdpcp, a PCP Protein Required for Ciliogenesis, Regulates Directional Cell Migration and Cell Polarity by Direct Modulation of the Actin Cytoskeleton. PLoS Biology, 11 (11). ISSN 1544-9173

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Abstract

Planar cell polarity (PCP) regulates cell alignment required for collective cell movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question of the role of the cilium in PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and collective cell movement, but the underlying mechanism is unknown. Here we show Wdpcp can regulate PCP by direct modulation of the actin cytoskeleton. These studies were made possible by recovery of a Wdpcp mutant mouse model. Wdpcp-deficient mice exhibit phenotypes reminiscent of Bardet-Biedl/Meckel-Gruber ciliopathy syndromes, including cardiac outflow tract and cochlea defects associated with PCP perturbation. We observed Wdpcp is localized to the transition zone, and in Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the transition zone, indicating Wdpcp is required for recruitment of proteins essential for ciliogenesis. Wdpcp is also found in the cytoplasm, where it is localized in the actin cytoskeleton and in focal adhesions. Wdpcp interacts with Sept2 and is colocalized with Sept2 in actin filaments, but in Wdpcp-deficient cells, Sept2 was lost from the actin cytoskeleton, suggesting Wdpcp is required for Sept2 recruitment to actin filaments. Significantly, organization of the actin filaments and focal contacts were markedly changed in Wdpcp-deficient cells. This was associated with decreased membrane ruffling, failure to establish cell polarity, and loss of directional cell migration. These results suggest the PCP defects in Wdpcp mutants are not caused by loss of cilia, but by direct disruption of the actin cytoskeleton. Consistent with this, Wdpcp mutant cochlea has normal kinocilia and yet exhibits PCP defects. Together, these findings provide the first evidence, to our knowledge, that a PCP component required for ciliogenesis can directly modulate the actin cytoskeleton to regulate cell polarity and directional cell migration.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cui, Cccui@pitt.eduCCUI
Chatterjee, B
Lozito, TPtpl9@pitt.eduTPL9
Zhang, Z
Francis, RJrfrancis@pitt.eduRFRANCIS
Yagi, Hhisato@pitt.eduHISATO
Swanhart, LM
Sanker, Ssus48@pitt.eduSUS48
Francis, D
Yu, Q
San Agustin, JT
Puligilla, C
Chatterjee, T
Tansey, T
Liu, Xxil78@pitt.eduXIL78
Kelley, MW
Spiliotis, ET
Kwiatkowski, AVadamkwi@pitt.eduADAMKWI
Tuan, Rrst13@pitt.eduRST13
Pazour, GJ
Hukriede, NAhukriede@pitt.eduHUKRIEDE
Lo, CWcel36@pitt.eduCEL36
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorScott, Matthew PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 November 2013
Date Type: Publication
Journal or Publication Title: PLoS Biology
Volume: 11
Number: 11
DOI or Unique Handle: 10.1371/journal.pbio.1001720
Schools and Programs: School of Medicine > Cell Biology
School of Medicine > Developmental Biology
School of Medicine > Orthopaedic Surgery
Refereed: Yes
ISSN: 1544-9173
Date Deposited: 30 Jan 2014 17:57
Last Modified: 17 Sep 2020 13:01
URI: http://d-scholarship.pitt.edu/id/eprint/20404

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