title: Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation.
abstract: The primary cilium acts as a transducer of extracellular stimuli into intracellular signaling [1, 2]. Its regulation, particularly with respect to length, has been defined primarily by genetic experiments and human disease states in which molecular components that are necessary for its proper construction have been mutated or deleted [1]. However, dynamic modulation of cilium length, a phenomenon observed in ciliated protists [3, 4], has not been well-characterized in vertebrates. Here we demonstrate that decreased intracellular calcium (Ca(2+)) or increased cyclic AMP (cAMP), and subsequent protein kinase A activation, increases primary cilium length in mammalian epithelial and mesenchymal cells. Anterograde intraflagellar transport is sped up in lengthened cilia, potentially increasing delivery flux of cilium components. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases mechanotransductive signaling. This adaptive response is blocked when the autosomal-dominant polycystic kidney disease (ADPKD) gene products, polycystin-1 or -2, are reduced. Dynamic regulation of cilium length is thus intertwined with cilium-mediated signaling and provides a natural braking mechanism in response to external stimuli that may be compromised in PKD.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Besschetnova
authors.forename: Elona
authors.initials: E
authors.lastname: Kolpakova-Hart
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Guan
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D002923:Cilia / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D015398:Signal Transduction
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases