title: A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.
abstract: Ciliogenesis precedes lineage-determining signaling in skin development. To understand why, we performed shRNA-mediated knockdown of seven intraflagellar transport proteins (IFTs) and conditional ablation of Ift-88 and Kif3a during embryogenesis. In both cultured keratinocytes and embryonic epidermis, all of these eliminated cilia, and many (not Kif3a) caused hyperproliferation. Surprisingly and independent of proliferation, ciliary mutants displayed defects in Notch signaling and commitment of progenitors to differentiate. Notch receptors and Notch-processing enzymes colocalized with cilia in wild-type epidermal cells. Moreover, differentiation defects in ciliary mutants were cell autonomous and rescued by activated Notch (NICD). By contrast, Shh signaling was neither operative nor required for epidermal ciliogenesis, Notch signaling, or differentiation. Rather, Shh signaling defects in ciliary mutants occurred later, arresting hair follicle morphogenesis in the skin. These findings unveil temporally and spatially distinct functions for primary cilia at the nexus of signaling, proliferation, and differentiation.
authors.affiliation: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Ezratty
authors.forename: Nicole
authors.initials: N
authors.lastname: Stokes
authors.forename: Sophia
authors.initials: S
authors.lastname: Chai
authors.forename: Alok S
authors.initials: AS
authors.lastname: Shah
authors.forename: Scott E
authors.initials: SE
authors.lastname: Williams
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018859:Hair Follicle / Q000166:cytology; D053823:Hedgehog Proteins / Q000378:metabolism; D007698:Kinesis; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; C560584:IFT74 protein, mouse; D051880:Receptors, Notch; C465570:Shh protein, mouse; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins