title: Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu.
abstract: Proper regulation of Indian hedgehog (Ihh) signaling is vital for chondrocyte proliferation and differentiation in the growth plate. Its dysregulation causes skeletal dysplasia, osteoarthritis or cartilaginous neoplasia. Here, we show that Suppressor of fused (Sufu) and Kif7 are essential regulators of Ihh signaling. While Sufu acts as a negative regulator of Gli transcription factors, Kif7 functions both positively and negatively in chondrocytes. Kif7 plays a role in the turnover of Sufu and the exclusion of Sufu-Gli complexes from the primary cilium. Importantly, halving the dose of Sufu restores normal hedgehog pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory activity of Sufu. Furthermore, Kif7 also inhibits Gli transcriptional activity in the chondrocytes when Sufu function is absent. Therefore, Kif7 regulates the activity of Gli transcription factors through both Sufu-dependent and -independent mechanisms.
authors.affiliation: Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Shu-Hsuan C
authors.initials: SH
authors.lastname: Hsu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Chunying
authors.initials: C
authors.lastname: Yu
authors.forename: Zhu Juan
authors.initials: ZJ
authors.lastname: Li
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006132:Growth Plate / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490763:Sufu protein, mouse; C543639:Kif7 protein, mouse; D016547:Kinesins