The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies

Abstract

The primary cilium protrudes from the cell surface and acts as a sensor for chemical and mechanical growth cues, with receptors for a number of growth factors (PDGFα, Hedgehog, Wnt, Notch) concentrated within the ciliary membrane. In normal tissues, the cilium assembles after cells exit mitosis and is resorbed as part of cell cycle re-entry. Although regulation of the cilium by cell cycle transitions has been appreciated for over 100 years, only recently have data emerged to indicate the cilium also exerts influence on the cell cycle. The resorption/protrusion cycle, regulated by proteins including Aurora-A, VHL, and GSK-3β, influences cell responsiveness to growth cues involving cilia-linked receptors; further, resorption liberates the ciliary basal body to differentiate into the centrosome, which performs discrete functions in S-, G2-, and M-phase. Besides these roles, the cilium provides a positional cue that regulates polarity of cell division, and thus directs cells towards fates of differentiation versus proliferation. In this review, we summarize the specific mechanisms mediating the cilia-cell cycle dialog. We then emphasize the examples of polycystic kidney disease (PKD), nephronopthisis (NPHP), and VHL-linked renal cysts as cases in which defects of ciliary function influence disease pathology, and may also condition response to treatment.

Fig. 1

Primary cilia disassembly prior to mitosis. The primary cilium present in G0/G1 phase starts to disassemble at G1-S transition, and is completely resorbed at early prophase. In some descriptions of quiescent cultured cells stimulated to reenter cell cycle by administration of serum, the primary cilium reassembles after disassembly at G1-S and is present during DNA and centriole duplication at S phase, and centriole maturation at G2 phase. Other reports describe two waves of deciliation, with some cells losing cilia prior to G1/S transition and the remainder losing cilia at the end of G2 phase

Fig. 2

Cilia disassembly at the G1-S transition. Activation of Aurora A, NIMA kinases and phosphorylation of Tectex-1 induces cilia resorption, whereas activity of Nde1 and INPPE5 blocks this process. The disassembly of cilia triggers phosphorylation and inactivation of pRb leading to cell cycle progression. Aurora A can be activated by PIFO and by inactivation of VHL to regulate cilia disassembly

Fig. 3

Ciliary signaling pathways implicated in control of cell proliferation. Mechanical sensation of cilia induced by fluid flow activates the LKb1-AMPK pathway in a calcium independent manner and inhibits mTOR1 pathway. Mechanical flow induces activation of PC1 and PC2 and results in elevation of internal calcium level, which suppresses cAMP signaling. In addition, calcium is required for PC1-CT targeting into the nucleus. PC1 also activates JAK2, which induces gene expression that promotes cell cycle progression. Ligand binding of PDGFRα in the cilia activates Raf-ERK pathway. Activation of cAMP signaling promotes PKA and AKAP activity, triggering cell cycle progression, whereas calcium inhibits this pathway. In addition, aberrant activation of wnt or hedgehog pathway stimulates cell cycle progression

Fig. 4

Oriented cell division regulated by cilia. Ciliary protein IFT88 (red ball, semi-transparent) is localized at the basal body of the cilium and at the centriole during spindle formation. Formation of astral microtubules (green lines) requires IFT88, which is essential for proper spindle orientation. Dysfunction of IFT88 results in malformation of astral microtubules leading to misoriented cell division