16-P005 Mutations in the lethal ciliopathy Meckel–Gruber syndrome alter the subcellular distribution of actin-binding proteins and disrupt the actin cytoskeleton

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Adams, Matthew ; Dawe, Helen ; Wheway, Gabrielle ; Szymanska, Katarzyna ; Logan, Clare ; Noegel, Angelika ; Gull, Keith ; Johnson, Colin (2009)
  • Publisher: Elsevier BV
  • Journal: Mechanisms of Development (issn: 0925-4773, vol: 126)
  • Related identifiers: doi: 10.1016/j.mod.2009.06.696
  • Subject: Developmental Biology | Embryology
    mesheuropmc: macromolecular substances

MKS3, encoding a novel trans-membrane receptor, meckelin with similarity to frizzled proteins, is mutated in Meckel–Gruber syndrome (MKS), an autosomal recessive lethal ciliopathy.\ud \ud Meckelin is a ciliary protein, but it also localises to the actin cytoskeleton at baso-lateral and basal cell surfaces. Filamin A (FLNa) and specific isoforms of nesprin-2 are actin-binding proteins (ABP) that interact with meckelin. Both are important for maintenance and remodelling of the actin cytoskeleton at the cell membrane and nuclear envelope. Meckelin and FLNa localised throughout ciliogenesis and in post-mitotic ciliated cells. However, a meckelin–nesprin-2 interaction was seen only during early ciliogenesis prior to the establishment of cell polarity and centriole migration; crucial steps in cilia formation. siRNA knockdown of meckelin caused loss of cilia and failure of centriole migration. This was also seen for FLNa and nesprin-2 indicating that mutation of ABPs could lead, or contribute, to a ciliopathy phenotype.\ud \ud In MKS patient fibroblasts, nuclear membrane architecture was distorted and cell-migration reduced; both indicative of disruption of the actin cytoskeleton. In addition, RhoA-GTPase activity was increased. Small GTPases are key regulators of actin assembly and remodelling pathways and the appearance of actin stress fibres was concurrent with this increased activity. Both FLNA and nesprin-2 were redirected to these fibres showing loss of meckelin altered distribution of ABPs.\ud \ud These novel findings suggest the actin cytoskeleton and actin-binding proteins play a crucial role in ciliogenesis and cilia function. This has important implications for defining the ciliopathy phenotype and determining the multi-functional role of ciliary proteins.
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