The dynamic cilium in human diseases

Abstract

Cilia are specialized organelles protruding from the cell surface of almost all mammalian cells. They consist of a basal body, composed of two centrioles, and a protruding body, named the axoneme. Although the basic structure of all cilia is the same, numerous differences emerge in different cell types, suggesting diverse functions. In recent years many studies have elucidated the function of 9+0 primary cilia. The primary cilium acts as an antenna for the cell, and several important pathways such as Hedgehog, Wnt and planar cell polarity (PCP) are transduced through it. Many studies on animal models have revealed that during embryogenesis the primary cilium has an essential role in defining the correct patterning of the body. Cilia are composed of hundreds of proteins and the impairment or dysfunction of one protein alone can cause complete loss of cilia or the formation of abnormal cilia. Mutations in ciliary proteins cause ciliopathies which can affect many organs at different levels of severity and are characterized by a wide spectrum of phenotypes. Ciliary proteins can be mutated in more than one ciliopathy, suggesting an interaction between proteins. To date, little is known about the role of primary cilia in adult life and it is tempting to speculate about their role in the maintenance of adult organs. The state of the art in primary cilia studies reveals a very intricate role. Analysis of cilia-related pathways and of the different clinical phenotypes of ciliopathies helps to shed light on the function of these sophisticated organelles. The aim of this review is to evaluate the recent advances in cilia function and the molecular mechanisms at the basis of their activity.

Figure 1

Cilia with different structures and primary cilia in diverse cell types and tissues. (A) Cross section of the 9+0 axonemal structure of the non-motile primary cilium. (B) Cross section of the 9+2 axonemal structure of the motile cilium with the motor molecules. (C) Primary cilia on Madin-Darby canine kidney (MDCK) cells. Cilia were stained with anti-α tubulin acetylated (red), basal bodies with anti-γ tubulin (green) and nuclei with 4',6-diamidino-2-phenylindole (DAPI). (D) Primary cilia in the ganglionic eminence of a brain at E12.5. Cilia were revealed by anti-adenylyl cyclase III (green), a marker specific for neuronal cilia, and nuclei were stained with DAPI. (E) Primary cilia in the renal tubules of a mouse at P7. Cilia were stained with anti-α tubulin acetylated (red) and dashed lines indicate the shape of the tubules. (F) Primary cilia in the limb bud in a mouse at P0. Cilia (indicated by arrows) were revealed with anti-α tubulin acetylated (red).

Figure 2

A summary of the pathways transduced by the primary cilium. The primary cilium is indicated in yellow with its basis formed by the basal body. In response to fluid flow, Polycystin 1 (PC1) and Polycystin 2 (PC2) are able to control the cell cycle. The platelet-derived growth factor alpha (PDGFα) signaling controls cell cycle and is transduced through the primary cilium. Vangl2 and Inv localize to primary cilia. Vangl2 is important for the planar cell polarity (PCP) pathway. Inv is the molecular switch between the PCP and Wnt pathways. Sonic hedgehog (Shh) signaling acts through Smoothened (Smo) that localizes to the primary cilium.