[HTML][HTML] A role for the primary cilium in Notch signaling and epidermal differentiation during skin development

EJ Ezratty, N Stokes, S Chai, AS Shah, SE Williams… - Cell, 2011 - cell.com
EJ Ezratty, N Stokes, S Chai, AS Shah, SE Williams, E Fuchs
Cell, 2011cell.com
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 …
Summary
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.
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