The extracellular matrix and ciliary signaling
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.
Section snippets
The cilia is a platform for signaling by receptors that influence adhesion
Although the cilium is a relatively small structure, the ciliary membrane is the obligate site of action for receptors for some signaling systems that profoundly condition cell growth, morphology, and adhesion, and a specialized site of action for additional signaling receptors (Figure 2). To summarize some of the better-studied ciliary functions, the polycystins (PC1 and PC2 [13, 14]) are encoded by the PKD1 and PKD2 genes, and are commonly mutated in autosomal dominant polycystic kidney
Cilia-mediated response to ECM
The bulk of research on the effect of mechanical cues interpreted through cilia has dealt with organ systems in which cilia protrude into fluid-filled lumens or ventricles, or in tissue culture experiments with cilia pointing into the medium, with these stimuli either specifying directional migration during organogenesis, polarized cell division, or programs of differentiation (e.g. [36, 37, 38•, 39, 40]). However, a growing number of studies emphasize mechanical stimuli arising through ciliary
ECM changes in ciliopathies
Cilia are commonly structurally defective and ciliary signaling is disrupted in ‘ciliopathies’ such as polycystic kidney disease (PKD), nephronophthisis (NPHP), Bardet–Biedl syndrome (BBS), and others, with these diseases characterized by abnormal cell–environment interactions. These defects commonly include extensive fibrosis within affected organs [57, 58, 59, 60, 61, 62]. Characteristics of the fibrosis observed in cystic kidney diseases includes early changes in epithelial cell polarity and
Control of ciliary dynamics by proteins with cell adhesion functions: emerging mechanisms
Over the past 4 years, a number of studies have elucidated the signaling machinery that controls ciliary protrusion and retraction during cell cycle, and highlighted interactions with proteins that regulate cell adhesion (reviewed partly in [3, 6]). A growing number of reports indicate that changes in ECM-interacting proteins and cell junctional proteins such as galectin-7, celsr2 and celsr3 specifically affect the process of ciliogenesis [87, 88•, 89]. This ECM contribution is augmented by
Conclusion
In conclusion, evidence continues to amass in support of the idea that cilia play important roles in cellular homeostasis, based on their ability to integrate chemical cues and flow and compression forces. Disruptions in cilia deregulate cell growth and polarity, and produce an extracellular environment, and frequent fibrosis (Figure 4). In turn, disruptions in the extracellular environment alter the signals received by cilia, again influencing cell growth properties. Given the rapidly
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
TS-N and EAG were supported by ROI CAG3366.
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