Role of primary cilia in non-dividing and post-mitotic cells

Abstract

The essential role of primary (non-motile) cilia during the development of multi-cellular tissues and organs is well established and is underlined by severe disease manifestations caused by mutations in cilia-associated molecules that are collectively termed ciliopathies. However, the role of primary cilia in non-dividing and terminally differentiated, post-mitotic cells is less well understood. Although the prevention of cells from re-entering the cell cycle may represent a major chore, primary cilia have recently been linked to DNA damage responses, autophagy and mitochondria. Given this connectivity, primary cilia in non-dividing cells are well positioned to form a signaling hub outside of the nucleus. Such a center could integrate information to initiate responses and to maintain cellular homeostasis if cell survival is jeopardized. These more discrete functions may remain undetected until differentiated cells are confronted with emergencies.

The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

“…Upon cell cycle re-entry, cilia are actively dismantled prior to mitosis, releasing the basal body to function as a microtubule-organizing centre (MTOC) for spindle assembly. Multiple proteins that play important ciliary roles are also involved in cell cycle regulation: for example, Aurora Kinase A (AurA), Polo Like Kinase-1 (Plk1), and Anaphase Promoting Complex (APC) are all key regulators of centrosome function and ciliary disassembly, as well as mitotic progression (reviewed in [5]).…”

Development and Evolutionary Constraints in Animals

“…Since then, it has become apparent that they do not only function as sensory organelles, but also have a key function in intercellular signaling (e.g. Dawe et al 2007, Ludeman et al 2014, Walz 2017. Signaling in the cilium is involved in the organization of most, if not all developmental processes, including left-right patterning, cell migration, re-entry of cells into the cell cycle (proliferation), cell size, cell shape, specification of the plane of cell division, apoptosis and cell fate decisions.…”

“…Signaling in the cilium is involved in the organization of most, if not all developmental processes, including left-right patterning, cell migration, re-entry of cells into the cell cycle (proliferation), cell size, cell shape, specification of the plane of cell division, apoptosis and cell fate decisions. For example, in vertebrates an important role of cilia is the coordination of a many pathways, including the Sonic hedgehog (Shh),Wnt, TGFβ, LKB1 and Hippo pathways (Breunig et al 2008, Ohazama et al 2009, Lancaster et al 2011, Basten & Giles 2013, Ke & Yang 2014, Walz 2017. Underlining the crucial importance of cilia in development and tissue homeostasis is the wide range and common occurrence of diseases that are caused by dysfunctional cilia, so-called ciliopathies, which include left-right patterning defects, polycystic kidney disease, retinal degeneration, diabetes, Meckel Gruber syndrome, microcephaly and cancer (e.g.…”

“…Recent research has shown that the cell cycle is not so much regulating centrosome and cilium dynamics, but contrastingly, the dynamics of the centrosome and primary cilium actively regulate cell cycle progression and arrest or exit followed by differentiation (Masuda & Sato 1984, Basten & Giles 2013, Goto et al 20132017, Ke & Yang 2014, Gabriel et al 2016, Walz 2017. For instance, the presence of the primary cilium appears to block cell division, while primary ciliary resorption is thought to unblock cell division and the length of the cilium influences cell cycle duration, with cell cycle length influencing cell fate decisions.…”

The primary cilium dampens proliferative signaling and represses a G2/M transcriptional network in quiescent myoblasts

“…Upon cell cycle re-entry, cilia are actively dismantled prior to mitosis, releasing the basal body to function as a microtubule-organizing centre (MTOC) for spindle assembly. Multiple proteins that play important ciliary roles are also involved in cell cycle regulation: for example, Aurora Kinase A (AurA), Polo Like Kinase-1 (Plk1), and Anaphase Promoting Complex (APC) are all key regulators of centrosome function and ciliary disassembly, as well as mitotic progression (reviewed in (5)). Thus, the current understanding is that the cilium exerts a check on cell cycle progression (reviewed in (6)) and that disassembly of the cilium is a prerequisite for cell cycle re-entry (7).…”