Linking the Primary Cilium to Cell Migration in Tissue Repair and Brain Development.

Primary cilia are unique sensory organelles that coordinate cellular signaling networks in vertebrates. Inevitably, defects in the formation or function of primary cilia lead to imbalanced regulation of cellular processes that causes multisystemic disorders and diseases, commonly known as ciliopathies. Mounting evidence has demonstrated that primary cilia coordinate multiple activities that are required for cell migration, which, when they are aberrantly regulated, lead to defects in organogenesis and tissue repair, as well as metastasis of tumors. Here, we present an overview on how primary cilia may contribute to the regulation of the cellular signaling pathways that control cyclic processes in directional cell migration.

Cilia and coordination of signaling networks during heart development.

Primary cilia are unique sensory organelles that coordinate a wide variety of different signaling pathways to control cellular processes during development and in tissue homeostasis. Defects in function or assembly of these antenna-like structures are therefore associated with a broad range of developmental disorders and diseases called ciliopathies. Recent studies have indicated a major role of different populations of cilia, including nodal and cardiac primary cilia, in coordinating heart development, and defects in these cilia are associated with congenital heart disease. Here, we present an overview of the role of nodal and cardiac primary cilia in heart development.

TGF-ß signaling is associated with endocytosis at the pocket region of the primary cilium.

Transforming growth factor ß (TGF-ß) signaling is regulated by clathrin-dependent endocytosis (CDE) for the control of cellular processes during development and in tissue homeostasis. The primary cilium coordinates several signaling pathways, and the pocket surrounding the base and proximal part of the cilium is a site for CDE. We report here that TGF-ß receptors localize to the ciliary tip and endocytic vesicles at the ciliary base in fibroblasts and that TGF-ß stimulation increases receptor localization and activation of SMAD2/3 and ERK1/2 at the ciliary base. Inhibition of CDE reduced TGF-ß-mediated signaling at the cilium, and TGF-ß signaling and CDE activity are reduced at stunted primary cilia in Tg737orpk fibroblasts. Similarly, TGF-ß signaling during cardiomyogenesis correlated with accumulation of TGF-ß receptors and activation of SMAD2/3 at the ciliary base. Our results indicate that the primary cilium regulates TGF-ß signaling and that the ciliary pocket is a compartment for CDE-dependent regulation of signal transduction.