Axo-Ciliary Interactions and Functional Specialization of Beta Cell Primary Cilia
Nikolai Klena
Primary cilia are nearly ubiquitous among mammalian cell types. These 9-fold microtubule (MT)-based structures contain MT doublets that transition into singlets and are historically thought to be present as one per cell. Unlike motile cilia, primary cilia do not actively beat but instead function in mechanotransduction and as signaling hubs in pathways such as Sonic Hedgehog and TGF-β. Multiple pancreatic cell types contain primary cilia, and conditional knockout of cilia in beta cells results in reduced insulin secretion and impaired glucose metabolism. However, the mechanisms by which cilia regulate glucose metabolism and insulin secretion remain unclear. We employed an imaging-based approach using volume electron microscopy and ultrastructural expansion microscopy to characterize beta cell primary cilia in their native context.
Using these complementary approaches, we found that primary cilia in islets are nearly fully embedded within a ciliary pocket and exhibit disorganized ciliary MT architecture, lacking motility components. The distal ends of beta cell primary cilia were frequently in contact with membranes of diverse cell types—both within and beyond islets—including alpha cells, blood vessels, acinar cells, and notably, cholinergic neurons. We observed that these putative axo-ciliary synapses resemble functional synapses, as evidenced by synaptic vesicle density and presynaptic machinery localized at the ciliary interface. We further identified that 20% of beta cells harbor two primary cilia with two complete centrosomes, and these cells exhibit elevated calcium signaling compared to other beta cells. Finally, beta cells undergoing glucose-stimulated insulin secretion in culture showed increased intraflagellar transport within the cilium, indicative of enhanced signaling activity. Together, these findings advance our mechanistic understanding of ciliary function in glucose metabolism and beta cell homeostasis.
