antagonistic and cooperative actions of kif7 and sufu define graded intracellular gli activities in hedgehog signaling敌对的和合作的行为kif7和sufu定义分级在刺猬信号细胞内gli活动.pdfVIP

Antagonistic and Cooperative Actions of Kif7 and Sufu Define Graded Intracellular Gli Activities in Hedgehog Signaling 1,2 3 1 1 1 Kelvin King Lo Law , Shigeru Makino , Rong Mo , Xiaoyun Zhang , Vijitha Puviindran , Chi- chung Hui1,2* 1 Program in Developmental Stem Cell Biology, The Hospital for Sick Children, Toronto Medical Discovery Tower, Toronto, Ontario, Canada, 2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada, 3 Mutagenesis and Genomics Team, RIKEN BioResource Center, Koyadai, Tsukuba, Ibaraki, Japan 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 naıve 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. Citation: Law