Linking the Primary Cilium to Cell Migration in Tissue Repair and Brain Development

Abstract

Primary cilia are unique sensory organelles that coordinate cellular signaling networks in vertebrates. Inevitably, defects in the formation or function of primary cilia lead to imbalanced regulation of cellular processes that causes multisystemic disorders and diseases, commonly known as ciliopathies. Mounting evidence has demonstrated that primary cilia coordinate multiple activities that are required for cell migration, which, when they are aberrantly regulated, lead to defects in organogenesis and tissue repair, as well as metastasis of tumors. Here, we present an overview on how primary cilia may contribute to the regulation of the cellular signaling pathways that control cyclic processes in directional cell migration.

Keywords: cell migration; cell polarity; cellular signaling; development; primary cilia; tissue repair.

Figure 1.

Outline of the primary cilium and modes of cell migration. (a) Primary cilia are microtubule (MT)-based, solitary organelles that emanate from the centrosomal mother centriole (basal body, BB) at the cell surface during growth arrest in most vertebrate cell types. An invagination at the cell membrane forms the ciliary pocket, in which transition fibers aid the docking of the BB to the periciliary membrane. The ciliary necklace is part of the ciliary pore complex, which functions as a diffusion barrier for the trafficking of proteins into and out of the cilium. The Golgi apparatus lies in close proximity to the base of the primary cilium. (b) The axoneme of the cilium comprises nine outer doublets of MTs that extend from the A and B subfibers of triplet MTs in the basal body. (c) The periciliary membrane is a site for the exocytosis and clathrin-dependent endocytosis in the dynamic trafficking of membrane and axonemal proteins into and out of the cilium across the ciliary pore complex. (d) Hypothesis on cellular morphologies and ciliary orientation in various migration modes. The orientation of the primary cilium toward the leading edge in 2D lamellipodium-based migration is illustrated with an immunofluorescence microscopy image of a fibroblast migrating into the wound of a scratch assay. The primary cilium (the open arrow) and arrays of microtubules projecting from the centrosome are stained with anti-acetylated α-tubulin (in blue). Source: Adapted with permission from Christensen and colleagues (2013). The lower insert shows the fibroblast primary cilium protruding from the ciliary pocket by scanning electron microscopy analysis. Micrograph: Johan Kolstrup, Peter Satir. (e) Fibroblast (1) lamellipodium formation and reorientation of the cilia–centrosome axis. Initial posterior positioning of the nucleus (2) is followed by reorganization of the actin cytoskeleton, and reorientation of the cilia–centrosome axis (2). Migration is initiated as the cilium points forward (3), and actin forces the membrane in the direction of the signal (4). (f) Tangentially migrating neurons extend a leading process in the direction of migration (1). Movement is a two-step process, consisting of pushing (2) and pulling (3) forces. First, a swelling occurs containing the Golgi–centrosome axis, including the primary cilium. This event is accompanied by pushing forces of actin or myosin at the posterior end (2). Simultaneously, pulling forces mediated by anterior MTs result in nuclear translocation (3). During nuclear translocation, the primary cilium may transiently be resorbed (Baudoin et al. 2012). Abbreviations: CCV, clathrin-coated vesicle; CMACs: cell-matrix adhesion complexes; CS, centriolar satellites; EE: early endosome; GDV, ­Golgi-derived vesicle. Color image available online at http://bioscience.oxfordjournals.org.

Figure 2.

(a) Schematic overview of ciliary signaling systems. The yellow segment of the cilium illustrates the inversin compartment. (b) Specified ciliary signaling pathways may promote (+) the vesicular trafficking and targeting of proteins to the leading edge of the migrating cell to control cell polarity processes. Insert: Localization of the calcium–hydrogen ion exchanger 1 (NHE1, in green) to the leading edge lamellipodium in a migrating fibroblasts. Tracks of microtubules (MT) were stained with anti-α-tubulin (in blue) and F-actin with phalloidin (in magenta). The arrows indicate the direction of NHE1 translocation. Source: Adapted with permission from Clement and colleagues (2013b). Abbreviations: ECM, extracellular matrix; GPCR, G-protein coupled receptor; Hh, Hedgehog; RTK, Receptor tyrosine kinase; TGFβ, transforming growth factor beta; Wnt, wingless/int. Color image available online at http://bioscience.oxfordjournals.org.