the secrets of vision and obesity in the ciliated neurons of C. elegans

I have never been fully aware of the power of primary cilia until now. Indeed, during the first year of my undergraduate degree we were told that people were still unaware of much of the functions of the primary cilium, and of the centrosome. Amazingly, primary cilia seem to be involved with some of the most crucial functions of the nervous system, and also with some unexpected mechanisms: these include, but are not limited to, sensing the external environment, regulating feeding behavior, chemosensation, regulation of fat metabolism and fat storage.

Cilia are microtubule-based structures, which can be motile (usually known as flagella) or non-motile. They can be found in most living organisms, and they are involved in a variety of processes, from allowing unicellular organisms to move, to allowing us to hear, smell, be capable of feeling heat and pressure, as well as to see. (Inglis P.N. et al. The sensory cilia of Caenorhabditis elegans (March 8, 2007), Wormbook, ed. The C. elegans Research Community, Wormbook, doi/10.1895/wormbook.1.126.2, http://www.wormbook.org)

It might help to see how fundamental cilia can be to processes apparently complex like eyesight to know that some dinoflagellate species reflect light onto a flagellum, which is thought to be the main locus of photoreceptor location: these flagella then allow these organisms to carry out successful phototaxis, moving towards the light. This might suggest that indeed primitive eyes evolved from cellular organelles very common among eukaryotes, and able to carry out additional functions (G. Kreimer, Protist 1999; 150: 311).

Worms (C.elegans, to be exact) have been recently shown to be excellent model organisms for the study not only of IFT, but also as animal models of Bardet-Biedl Syndrome, or BBS. BBS is a polygenic disorder characterized by a variety of symptoms, including but not limited to severe obesity, polydactyly, impaired vision, kidney abnormalities, and learning disabilities. It was recently discovered that BBS is actually a ciliopathy, in which several genes involved in cilia function and IFT have been discovered to be mutated. These bbs genes were soon discovered to have similar effects and functions in mice and C. elegans. (Blaque et al. Cell Mol Life Sci 2006; 63: 2145-216)

Initially, it was discovered that BBS8 localised specifically at the basal bodies and centrosomes, and that it co-localised with a ciliary protein. A search for homologous genes in C. elegans revealed a series of BBS genes, which were then found to be expressed specifically in ciliated neurons; such genes could also be found in other ciliated organisms, but not in organisms lacking cilia. What is more amazing is that one of the bbs genes, specifically bbs-1, was found through a genetic screen for mutations that would intensify the fat storage phenotypes caused by tub-1 mutations. Tub-1 is the worm homologue of a very famous gene involved in fat storage regulation, more commonly known as tubby. (Mak et al. Nature Genetics 2006; 38: 363-368)

Tubby mice arose spontaneously, and later it was found that mutations in the tub gene were responsible for the phenotype. This brings us back to the link between obesity, cilia and the nervous system: tub is in fact mainly expressed in the hypothalamus (this in mammals), and in general in the central nervous system. Tub-related proteins, known as TULPs: their role in the nervous system is still being investigated. But what is thrilling is that tubby mice not only exhibit defects in fat storage, as the name suggests, but are also hearing and vision impaired, probably due to apoptosis of sensory neurons. (Carroll et al. Nat Rev Mol Cell Bio 2004; 5: 55-63)

With new studies showing the involvement of bbs proteins in intraflagellar transport, which is necessary for maintenance and building of cilia (Ou et al. Nature 2005; 436: 583-587) and tub-1 being a suggested cargo for intraflagellar transport (Mukhopadhyay et al. Cell Metabolism 2005; 2: 35-42), the complex links in the central nerous system between obesity, learning abilities and sensation might be soon explained by the elegant mechanisms of ciliary maintenance.