Cilia are hair-like microtubule based cellular appendages that extend 5-30 microns from the surface of most vertebrate cells. Since their initial discovery over a hundred years ago, cilia have been of interest to microbiologists and others studying the dynamics and physiological relevance of their motility. The more recent realization that immotile or primary cilia dysfunction is the basis of several human genetic disorders and diseases has brought the efforts of the biomedical research establishment to bear on this long overlooked and underappreciated organelle.
Several human genetic disorders caused by cilia defects have been identified, and include Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, Alstrom syndrome and orofaciodigital syndrome. One theme of these disorders is their multitude of clinical features such as blindness, cystic kidneys, cognitive deficits and obesity. The fact that many of these cilia disorders present with several features may be due to the ubiquitous nature of the primary cilium and their unrecognized roles in most tissues and cell types.
It is apparent that the functions of cilia, at least in part, are defined by the specific proteins that localize within and on the organelle. Indeed access of proteins and signaling modules into and out of the ciliary compartment appears to be tightly regulated. In order to better understand the physiological roles of cilia throughout the body, an understanding of the signaling proteins that localize to the cilium and the mechanisms behind cilia localization is needed.
The development of certain tools has allowed for the opportunity to test the hypothesis that certain clinical features of the ciliary disorder Bardet-Biedl Syndrome (BBS) are due to neuronal cilia dysfunction. Indeed, we have shown that mouse models of BBS fail to localize specific receptors to their neuronal cilia (Chapter 5). These data have set the ground work for more extensive investigations into neuronal cilia function. Further, this work suggests neuronal cilia dysfunction may contribute not only to the cognitive defects associated with ciliary disorders, but may also underlie the obesity observed in these disorders.