Seriously cilia: A tiny organelle illuminates evolution, disease, and intercellular communication

Abstract

The borders between cell and developmental biology, which have always been permeable, have largely dissolved. One manifestation is the blossoming of cilia biology, with cell and developmental approaches (increasingly complemented by human genetics, structural insights, and computational analysis) fruitfully advancing understanding of this fascinating, multifunctional organelle. The last eukaryotic common ancestor probably possessed a motile cilium, providing evolution with ample opportunity to adapt cilia to many jobs. Over the last decades, we have learned how non-motile, primary cilia play important roles in intercellular communication. Reflecting their diverse motility and signaling functions, compromised cilia cause a diverse range of diseases collectively called "ciliopathies." In this review, we highlight how cilia signal, focusing on how second messengers generated in cilia convey distinct information; how cilia are a potential source of signals to other cells; how evolution may have shaped ciliary function; and how cilia research may address thorny outstanding questions.

Keywords: ADPKD; BBSome; Foxj1; Hedgehog; LECA; PKA; PKD; cAMP; ciliation; ciliogenesis; polycystic; transition zone.

Figure 1 -. Motile and immotile cilia differ structurally and LECA possessed a sophisticated cilium

A) Most motile cilia (left) have an axoneme comprised of nine circumferential doublets and a central pair. Most primary cilia (right) have an axoneme lacking the central pair. B) A formulation of the eukaryotic tree of life, depicting major clades. Ciliated lineages are depicted with colored lines, unciliated groups are in black and lineages with both are in both. While some groups lack cilia (e.g., Rhodophyta), and some groups contain both ciliated and unciliated members (e.g., Chloroplastida), ciliated organisms exist in all extant clades. Thus, the last eukaryotic common ancestor was probably a ciliated protist. Figure modified from reference . C) Ciliated lineages share genes encoding ciliary proteins, including components of the LIFT system for transporting lipidated proteins. In the cilium, ARL3 triggers LIFT to deposit cargoes such as ARL13B and INPP5E into the ciliary membrane. Other evolutionarily ancient protein complexes involved in ciliary function include DISCO, a distal centriolar complex involved in forming distal appendages, DNAAFs involved in assembling dyneins, the transition zone controlling the protein composition of the ciliary membrane, IFT driving transport along the ciliary axoneme, the BBSome helping export select proteins from the cilium, the MIPs reinforcing the ciliary microtubules, and the central pair apparatus, radial spokes, and N-DRC that, together, coordinate the IDAs and ODAs that beat the cilia.

Figure 2 –. Ciliary Hedgehog signaling translates different ciliary protein composition into different transcriptional outputs.

In the absence of Hedgehog (HH) signals (left), PTCH is present in the cilium and keeps SMO out and inactive. Without active SMO in the cilium, GLI transcription factors are converted into a repressive form (GliR), translocate to the nucleus and keep the Hedgehog transcription program off. In the presence of HH signals (right), SMO accumulates in the cilium and converts GLI into an activator form (GliA) which induces the Hedgehog transcriptional program.

Figure 3 –. Polycystin channels protect the kidney from cystogenesis.

A) Polycystin channels are heterotetramers each comprised of one PKD1 subunit and three PKD2 subunits. Image of PDB 6A70 human PKD1/PKD2 complex (Su et al., 2018) created with UCSF ChimeraX. B) Almost all nephron epithelial cells project a Polycystin channel-bearing cilium into the lumen through which filtrate flows. C) Removing cilia from nephron epithelial cells causes mild cystogenesis. Removing Polycystin function by abrogating either PKD1 or PKD2 causes severe cystogenesis. Removing both cilia and Polycystin function causes moderate cystogenesis, revealing cilia-dependent cyst activation (CDCA) (Ma et al., 2013).

Figure 4 –. Different ciliary environments facilitate specific signaling cascades

A) Left: When peripheral energy stores are depleted, Leptin levels fall, leading Leptin-responsive neurons in the hypothalamus to make AgRP, an inverse agonist of MC4R. In the absence of MC4R activity, ADCY3 in neuronal cilia does not generate cAMP, spurring feeding. Right: When peripheral energy stores are repleted, Leptin triggers hypothalamic neurons to make αMSH, an MC4R agonist (green). Stimulating MC4R induces ADCY3 to generate ciliary cAMP, suppressing feeding. B) cAMP generated in the cilium activates a ciliary pool of PKA to turn off Hedgehog signal transduction.

Figure 5 -. Some C. elegans cephalic male neuronal cilia release extracellular vesicles.

Mutations in rab-28 or bbs-8 increase ectocytosis of extracellular vesicles into the lumen surrounding the cilia.

Figure 6 –. Not all animal cells possess cilia.

For example, the skin is comprised of hair follicles and the interfollicular epidermis. Most cells making up the interfollicular epidermis are unciliated. In contrast, most cells of the hair follicle are ciliated. What controls which cells are ciliated and which are not remains unknown.

Figure 7 -. A model of ciliary involvement in neurological disease.

In Parkinson’s disease, dopaminergic neurons in the substantial nigra of the basal ganglia are lost. These neurons are supported by GDNF produced by cholinergic neurons in the striatum. A rare form of Parkinson’s disease is caused by gain-of-function mutations (e.g., G2019S) in a kinase, LRRK2, that disrupts cilia in the striatum. With compromised cilia, the cholinergic neurons do not respond to the Hedgehog signals produced by the dopaminergic neurons and, consequently, fail to produce GDNF, perhaps leading to the death of the dopaminergic neurons.