Primary Cilia and Signaling Pathways in Mammalian Development, Health and Disease

Abstract

Although first described as early as 1898 and long considered a vestigial organelle of little functional importance, the primary cilium has become one of the hottest research topics in modern cell biology and physiology. Primary cilia are nonmotile sensory organelles present in a single copy on the surface of most growth-arrested or differentiated mammalian cells, and defects in their assembly or function are tightly coupled to many developmental defects, diseases and disorders. In normal tissues, the primary cilium coordinates a series of signal transduction pathways, including Hedgehog, Wnt, PDGFRα and integrin signaling. In the kidney, the primary cilium may function as a mechano-, chemo- and osmosensing unit that probes the extracellular environment and transmits signals to the cell via, e.g., polycystins, which depend on ciliary localization for appropriate function. Indeed, hypomorphic mutations in the mouse ift88 (previously called Tg737) gene, which encodes a ciliogenic intraflagellar transport protein, result in malformation of primary cilia, and in the collecting ducts of kidney tubules this is accompanied by development of autosomal recessive polycystic kidney disease (PKD). While PKD was one of the first diseases to be linked to dysfunctional primary cilia, defects in this organelle have subsequently been associated with many other phenotypes, including cancer, obesity, diabetes as well as a number of developmental defects. Collectively, these disorders of the cilium are now referred to as the ciliopathies. In this review, we provide a brief overview of the structure and function of primary cilia and some of their roles in coordinating signal transduction pathways in mammalian development, health and disease.

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

“…Patients who have defects in ciliary motility develop retinal degeneration (Brown & Witman, 2014). It has also been shown that primary cilia coordinate a series of signaling pathways and regulate cell migration during the development of and during the process of wound healing (Veland, Awan, Pedersen, Yoder, & Christensen, 2009). …”

The Hedgehog signaling pathway in ovarian teratoma is stimulated by Sonic Hedgehog which induces internalization of Patched

“…It has been demonstrated that the primary cilia are required for Hh-Gli pathway regulation in mammalian development, where they act as a switch for turning the signaling on and off (34). However, the cilia are not required for the Drosophila Hh signaling, and the signaling events involving SuFu and Gli proteins are independent of cilia (43).…”

“…34). Therefore cells were stained for acetylated tubulin to check for primary cilia formation and possible colocalization with the pathway proteins.…”

Cilia and coordination of signaling networks during heart development

“…32,35,197 However, many Wnt signaling components, such as Fz3, Dvl, and β-catenin, localize to the ciliary/centrosomal axis, and dysregulated Wnt signaling has been reported in cells and tissues with disrupted ciliogenesis or basal body integrity. [198][199][200] Moreover, in the mouse inner ear, establishment of PCP was shown to depend on the formation of functional primary cilia. 201 However, other studies in mice and zebrafish reveal no obvious canonical or non-canonical Wnt phenotypes in cilia mutants, 202,203 emphasizing the importance of further studies in this area.…”