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Signaling through the Primary Cilium - PubMed

  • ️Mon Jan 01 2018

Review

Signaling through the Primary Cilium

Gabrielle Wheway et al. Front Cell Dev Biol. 2018.

Abstract

The presence of single, non-motile "primary" cilia on the surface of epithelial cells has been well described since the 1960s. However, for decades these organelles were believed to be vestigial, with no remaining function, having lost their motility. It wasn't until 2003, with the discovery that proteins responsible for transport along the primary cilium are essential for hedgehog signaling in mice, that the fundamental importance of primary cilia in signal transduction was realized. Little more than a decade later, it is now clear that the vast majority of signaling pathways in vertebrates function through the primary cilium. This has led to the adoption of the term "the cells's antenna" as a description for the primary cilium. Primary cilia are particularly important during development, playing fundamental roles in embryonic patterning and organogenesis, with a suite of inherited developmental disorders known as the "ciliopathies" resulting from mutations in genes encoding cilia proteins. This review summarizes our current understanding of the role of these fascinating organelles in a wide range of signaling pathways.

Keywords: Hedgehog; cell signaling; ciliopathies; development; developmental disorders; primary cilium.

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Figures

Figure 1
Figure 1

The structure of the primary cilium. (A) The primary cilium is formed on the apical surface of cells, from the basal body which is derived from the mother centriole. The daughter centriole stays associated, at roughly rightangles, surrounded by pericentriolar material. The basal body is located in a depression of membrane known as the ciliary pocket, and is connected to membrane here by transition fibers. The region where the central pair of microtubules in the basal body microtubule triplet grow to form the ciliary axoneme is called the transition zone. Here, Y-linkers connect the axoneme to the ciliary membrane. Protein and other cargos are transported from cilium base to tip by anterograde IFT particles and kinesin-2 motor. Protein and other cargos are transported from cilium tip to base by retrograde IFT particles and cytoplasmic dynein motor. (B) In cross-section the 9+0 formation of microtubule doublets can be seen in radial array, making up the ciliary axonome. It is formed of a ring of 9 pairs of post-translationally modified microtubules, with no central pair and no dynein arms.

Figure 2
Figure 2

Hedgehog signaling at the primary cilium in vertebrates. (A) In the unstimulated state, Ptc1 sits in the cilium membrane and represses and excludes Smoothened (Smo) from the cilium. Gli transcription factors are sequestered and suppressed by Suppressor of Fused (SuFu) at the tip of the primary cilium. (B) In the stimulated state, upon binding of Shh to Ptc1, the repression of Smo by Ptc1 is relieved, allowing Smo to enter the cilium and Ptc1 to leave the cilium. This then allows Smo to repress SuFu, relieving repression of Gli at the tip of the cilium. Gli is thus freed to be post-translationally modified to form Gli activator form (GliA), which is transported out of the cilium to the nucleus to activate expression of downstream target genes.

Figure 3
Figure 3

Canonical Wnt signaling at the primary cilium. (A) In the unstimulated “off state,” the Axin/APC/GSK3-β “destruction complex” targets β-catenin to the proteasome for degradation, preventing β-catenin from entering the nucleus to activate gene expression. In the stimulated “on” state, Wnt ligands bind to a membrane-bound Frizzled (Fzd) receptor, which then binds LRP5/6, allowing it to recruit Axin. With Axin sequestered by LRP5/6, the Axin/APC/GSK3-β “destruction complex” can no longer degrade β-catenin, leaving it free to enter the nucleus, aided by AHI1, to interact with TCF and LEF transcription factors to activate transcription of Wnt target genes under TCF/LEF promoters. The Wnt signal is transduced via Disheveled (Dvl), which is recruited to the membrane and binds Axin upon stimulation. (B) The primary cilium controls the level of expression of Wnt target genes, via controlled degradation of Dvl by cilia proteins INVS and NPHP3, and by sequestering AHI1 at the cilium so it cannot aid translocation of β-catenin into the nucleus.

Figure 4
Figure 4

Non-canonical Wnt signaling at the primary cilium. Non-canonical Wnt ligands bind to Frizzled 3 (Fzd3) receptor, which triggers asymmetric localisation of Vangl2 in the cell. This pathway acts through Dvl to activate RhoA, and the JNK pathway, to stimulate Ca2+ release to stimulate remodeling of the actin cytoskeleton. This is dependent upon correct definition of cell polarity by basal body migration to the apical cell surface. This migration is regulated by Dvl, by transition zone proteins meckelin (TMEM67) and TMEM216 and by basal body protein MKS1. Inversin also plays a role.

Figure 5
Figure 5

Notch signaling through the primary cilium. A Notch receptor binds to a membrane-bound Delta or Jagged ligand on an adjacent cell, stimulating proteolytic cleavage of the Notch intracellular domain (NCID) by Presenilin, allowing NCID to translocate to the nucleus where it can activate downstream target genes in association with RBPj DNA binding protein. This is dependent on correct localisation of Presenilin to the basal body, controlled by ARF4 exocytosis.

Figure 6
Figure 6

Hippo signaling through the primary cilium. (A) In the unstimulated “off” state, MST1/2 phopsphorylates LATS1/2, resulting in the downstream phosphorylation and inactivation of YAP/TAZ. Phosphorylation of YAP/TAZ causes it to bind 14-3-3 and be retained in the cytoplasm, preventing it from complexing with TEAD1-4 to activate transcription of target genes. (B) In the ciliated “on” state, NPHP complex proteins bind MST1/2 at the basal body, and LATS1/2, preventing phosphorylation and activation of YAP/TAZ. YAP/TAZ is then free to enter the nucleus and complex with TEAD1-4 to activate transcription of target genes.

Figure 7
Figure 7

The ciliopathy spectrum. Schematic illustration of common features of ciliopathies, and severity of each ciliopathy along a spectrum from perinatal lethal to isolated retinal dystrophy. Key shows which phenotype is represented by each symbol.

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