Keeping the balance between proliferation and differentiation: the primary cilium

Abstract

Primary cilia are post-mitotic cellular organelles that are present in the vast majority of cell types in the human body. An extensive body of data gathered in recent years is demonstrating a crucial role for this organelle in a number of cellular processes that include mechano and chemo-sensation as well as the transduction of signaling cascades critical for the development and maintenance of different tissues and organs. Consequently, cilia are currently viewed as cellular antennae playing a critical role at the interphase between cells and their environment, integrating a range of stimuli to modulate cell fate decisions including cell proliferation, migration and differentiation. Importantly, this regulatory role is not just a consequence of their participation in signal transduction but is also the outcome of both the tight synchronization/regulation of ciliogenesis with the cell cycle and the role of individual ciliary proteins in cilia-dependent and independent processes. Here we review the role of primary cilia in the regulation of cell proliferation and differentiation and illustrate how this knowledge has provided insight to understand the phenotypic consequences of ciliary dysfunction.

Keywords: Cilia; cancer.; cell cycle; ciliopathies.

Fig. (1) The basic structure of cilia.

Schematic representation of the cilium showing the organization of the microtubule backbone (axoneme and basal body) and the process of IFT. The two main types of axoneme, 9+2 and 9+0 are shown and some examples of IFT particles are highlighted.

Fig. (2). The cell and ciliary cycle.

Simplified representation of the control of the cell cycle where we have incorporated ciliary proteins that have been described as directly implicated in cell cycle control. Immunocytochemistry images correspond to NIH3T3 fibroblasts in different stages of the cell cycle, stained with anti-acetylated tubulin (green) to visualize the primary cilium, anti-γ tubulin (green) for staining the centrosome and DAPI for the nucleus. Cyc: cyclin; CDK: cyclin dependent kinase.

Fig. (3). The primary cilium in signal transduction.

Schematic and simplified representation of the primary cilium and its role in the transduction of paracrine and Ca²⁺ signaling to ultimately control cellular homeostasis. Localization of PDGFRαα to the primary cilium is required for proper signaling upon activation by PDGF-AA (green). In Hh signaling, binding of Shh to PTC1 drives the translocation of the receptor outside of the primary cilium thus allowing the entry and accumulation of Smo in the ciliary compartment. This re-localization is required for the proper processing of the Gli transcription factors and is needed for correct Shh signaling (purple). The cilium and basal body proteins such as inversin/NPHP2 (Inv) and the BBSs are required for the modulation of Wnt signaling influencing the balance between canonical Wnt and PCP signaling (light blue). The ciliary localization of PC1 and PC2 is required to couple ciliary bending with Ca²⁺ signaling (yellow).