title: Antagonistic and cooperative actions of Kif7 and Sufu define graded intracellular Gli activities in Hedgehog signaling.
abstract: Graded Hedgehog (Hh) signaling governs the balance of Gli transcriptional activators and repressors to specify diverse ventral cell fates in the spinal cord. It remains unclear how distinct intracellular Gli activity is generated. Here, we demonstrate that Sufu acts universally as a negative regulator of Hh signaling, whereas Kif7 inhibits Gli activity in cooperation with, and independent of, Sufu. Together, they deter naïve precursors from acquiring increasingly ventral identity. We show that Kif7 is also required to establish high intracellular Gli activity by antagonizing the Sufu-inhibition of Gli2. Strikingly, by abolishing the negative regulatory action of Sufu, diverse ventral cell fates can be specified in the absence of extracellular Hh signaling. These data suggest that Sufu is the primary regulator of graded Hh signaling and establish that the antagonistic and cooperative actions of Kif7 and Sufu are responsible for setting up distinct Gli activity in ventral cell fate specification.
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors.forename: Kelvin King Lo
authors.initials: KK
authors.lastname: Law
authors.forename: Shigeru
authors.initials: S
authors.lastname: Makino
authors.forename: Rong
authors.initials: R
authors.lastname: Mo
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Vijitha
authors.initials: V
authors.lastname: Puviindran
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; C490763:Sufu protein, mouse; D000071676:Zinc Finger Protein GLI1; C543639:Kif7 protein, mouse; D016547:Kinesins