Primary cilia are signaling transduction conduits and the hedgehog isn't just a video game!
Opinion by Kasturi Pal, Ph.D.
Primary cilia are microtubule based cellular appendages arising for the apical surfaces of cells. Although long considered to be vestigial organelles, it has now been well established that these cellular structures serve as crucial cell signaling hubs, transducing extracellular signaling cues into intracellular biochemical pathways. For example, in the vertebrate system, the solitary primary cilium is indispensable for the functioning of the hedgehog signaling pathway. This pathway is crucial towards the development in vertebrates and directs appropriate differentiation information in embryonic cells among other functions. Defects in ciliogenesis, ciliary trafficking or signaling pathways result in a broad group of diseases grouped together as “ciliopathies”.
Although primary cilia are known to be crucial mediators of signal transduction pathways, tracking the kinetics of second messenger accumulation in the cilium of live cells was difficult to accomplish until very recently. By using live cell imaging and electrophysiological measurements the authors of this work demonstrated that sonic hedgehog (Shh) signaling elevates intraciliary calcium levels (Shh goes calcium crazy). The terminal effectors of Shh signaling are the Gli family transcription factors. In the basal or “off state” of the Shh pathway, cAMP activated protein kinase A (PKA) triggers proteolytic cleavage of the full length Gli molecules to generate the truncated repressor. In contrast, during the presence of Shh or the “on state” of the pathway full length Gli proteins are processed to an active form, which triggers expression of Shh target genes. Although, it has been shown that PKA is a part of the ciliary proteome (A proximity labeled cilia) and that it localizes to the basal bodies, at the base of the cilia (PKA - location location location), it was unknown how dynamic regulation of cAMP levels is maintained in the ciliary lumen. Moore et al using a cilia localized cAMP biosensor, demonstrated that Shh treatment attenuates the basal intraciliary cAMP levels. This lowering of cAMP in the cilia lumen is dependent on calcium influx through gadolinium sensitive calcium channels present in the cilia membrane which suppresses adenylyl cyclase 5 and 6. Surprisingly, this finding challenges previous notion in the field, which heavily pointed towards Smoothened dependent activation of Gαi (an inhibitory G protein which is involved in various signaling mechanicsm) in the cilia, which results in repression of adenylyl cyclase (which is a ubiquitous enzyme with several regulatory roles in the cell) - upon Shh stimulation (Sonic vs. Calcium).
Although this study identifies a novel player in Shh dependent processing of Gli transcription factors, the identity of the calcium channel remains unknown. It is also unclear how Shh goes on to activate calcium channels in the cilia membrane. Further work to uncover this mechanism may prove beneficial for developing inhibitory drugs against these Shh activated calcium channels, which can be useful for treating Shh driven tumors.