The extracellular matrix and ciliary signaling

The primary cilium protrudes like an antenna from the cell surface, sensing mechanical and chemical cues provided in the cellular environment. In some tissue types, ciliary orientation to lumens allows response to fluid flow; in others, such as bone, ciliary protrusion into the extracellular matrix allows response to compression forces. The ciliary membrane contains receptors for Hedgehog, Wnt, Notch, and other potent growth factors, and in some instances also harbors integrin and cadherin family members, allowing receipt of a robust range of signals. A growing list of ciliopathies, arising from deficient formation or function of cilia, includes both developmental defects and chronic, progressive disorders such as polycystic kidney disease (PKD); changes in ciliary function have been proposed to support cancer progression. Recent findings have revealed extensive signaling dialog between cilia and extracellular matrix (ECM), with defects in cilia associated with fibrosis in multiple contexts. Further, a growing number of proteins have been determined to possess multiple roles in control of cilia and focal adhesion interactions with the ECM, further coordinating functionality. We summarize and discuss these recent findings.

Introduction

In vertebrates and other complex metazoans, tissue organization is achieved and supported through a dialogue between extracellular signals and a trans-membrane interpretive machinery that coordinates appropriate assembly of intracellular cytoskeletal structures. Integrins mediate communication with the basement membrane; cadherins and desmosomal proteins mediate cell–cell communications. A growing number of studies now suggest that another structure, the cilium (Figure 1), also contributes to environmental sensing based on roles in receipt of mechanical and chemical cues. With rare exceptions (e.g. oncogenically transformed cells or lymphocytes, which are non-ciliated; lung epithelial cells, which are multiciliated [1]), most cells have a single protruding cilium. Although related mammalian structurally to the motile flagella of lower eukaryotes, such as Chlamydomonas, most cilia are non-motile, although again, rare exceptions of cells motile cilia exist, and some play important roles in development [2]. Structurally, a cilium is composed of 9 microtubule-based doublets organized in a circle around a hollow core, covered by a membrane, and extending 3–10 μm from the cell surface. The basal body that anchors the cell-proximal end of the cilium differentiates from the older (‘mother’) centriole of the centrosome as cells enter G1 or G0 after cytokinesis, as cilia protrude from the cell [3]. Cilia resorb, and the basal body is re-modified to function as part of a centrosome, in waves preceding S phase and G2/M. An excellent series of recent reviews have detailed ciliary ultrastructure, connections to cell cycle, and intracellular signaling defects associated with disease states [3, 4, 5, 6, 7].

In contrast to the broadly appreciated roles of cilia in receipt of flow or soluble cues, a growing body of literature connects ciliary function to control of cell adhesion, although the relationship has not been as broadly appreciated. While many cilia orient into lumens, others typically orient towards the extracellular matrix (ECM) (e.g. [8, 9, 10, 11, 12]). Receptors for many signaling proteins that influence cell adhesion, polarity, and interactions with the ECM localize expressly to the ciliary membrane; studies of ‘ciliopathies’, a group of hereditary diseases specifically associated with ciliary defects, clearly indicate aberrant cell–ECM interactions. We here summarize recent relevant studies.