RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 9 July 2014; doi:10.1038/nrm3839
O R G A N E L L E DY N A M I C S
KIF7 organizes cilia KIF7 destabilizes the GTP-bound tubulin cap to induce catastrophe and limit microtubule growth
Primary cilia are microtubule-based organelles that mediate the mammalian Hedgehog (HH) signalling pathway. The kinesin family member kinesin-like protein KIF7 is required for HH signal transduction. Although other kinesin motor proteins have been implicated in intracellular trafficking and the regulation of microtubule length, the specific role of KIF7 in the cilium remained elusive. He et al. now report that KIF7 binds to microtubule plus ends at cilia tips to control cilium length and structure, and to organize a specialized compartment that mediates HH signalling.
The authors showed that KIF7 localizes to the tip of cilia in mouse embryonic fibroblasts (MEFs) and in embryonic mesenchymal cells, whereas KIF7 bearing an amino acid substitution in the motor domain (KIF7L130P) was not detected at cilia tips. In addition, the authors noted that cilia from Kif7–/– or KIF7L130P MEFs, as well as from cells in the embryonic neural tube, were longer and less stable than cilia from wild-type cells, and also exhibited morphological defects. These findings suggest that KIF7 at the distal tips of primary cilia has a role in the regulation of cilia length, architecture and stability. Next, in human cell lines, the authors found that overexpressed KIF7 forms homodimers and colocalizes to microtubule bundles. The association with microtubules was mediated by the motor domain, which is in agreement with the finding that this domain is required for the proper localization of KIF7 in cilia. Interestingly, the authors found that KIF7, unlike most kinesins, did not diffuse or directionally move along microtubules in vitro. The authors went on to test whether KIF7 regulates microtubule growth by altering tubulin polymerization dynamics. Using a dynamic microtubule assay, they found that addition of the KIF7 motor domain
promoted microtubule shrinkage (catastrophe) and preferentially inhibited microtubule growth at the plus ends. Microtubule growth was not inhibited in the presence of a non-hydrolysable ATP analogue, which suggests that ATP hydrolysis is required for KIF7‑mediated regulation of microtubule plus-end dynamics. Moreover, time-lapse imaging revealed that the motor protein associated with GTP-bound tubulin at the growing plus end of microtubules during the growing phase and dissociated at the onset of catastrophe. Thus, KIF7 destabilizes the GTP-bound tubulin cap to induce catastrophe and limit microtubule growth. Finally, the authors showed that KIF7 was not required for intra flagellar transport or trafficking of components of the HH signalling pathway into cilia; however, KIF7 was crucial for the generation of a compartment at the cilium tip that ensured the proper localization and regulation of HH signalling. In summary, this study shows that KIF7 regulates tubulin dynamics to control both cilia structure and HH signalling. Andrea Du Toit ORIGINAL RESEARCH PAPER He, M. et al. The kinesin‑4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nature Cell Biol. http://dx.doi. org/10.1038/ncb2988 (2014)
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NATURE REVIEWS | MOLECULAR CELL BIOLOGY
VOLUME 15 | AUGUST 2014 © 2014 Macmillan Publishers Limited. All rights reserved
Copyright of Nature Reviews Molecular Cell Biology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
O R G A N E L L E DY N A M I C S
KIF7 organizes cilia KIF7 destabilizes the GTP-bound tubulin cap to induce catastrophe and limit microtubule growth
Primary cilia are microtubule-based organelles that mediate the mammalian Hedgehog (HH) signalling pathway. The kinesin family member kinesin-like protein KIF7 is required for HH signal transduction. Although other kinesin motor proteins have been implicated in intracellular trafficking and the regulation of microtubule length, the specific role of KIF7 in the cilium remained elusive. He et al. now report that KIF7 binds to microtubule plus ends at cilia tips to control cilium length and structure, and to organize a specialized compartment that mediates HH signalling.
The authors showed that KIF7 localizes to the tip of cilia in mouse embryonic fibroblasts (MEFs) and in embryonic mesenchymal cells, whereas KIF7 bearing an amino acid substitution in the motor domain (KIF7L130P) was not detected at cilia tips. In addition, the authors noted that cilia from Kif7–/– or KIF7L130P MEFs, as well as from cells in the embryonic neural tube, were longer and less stable than cilia from wild-type cells, and also exhibited morphological defects. These findings suggest that KIF7 at the distal tips of primary cilia has a role in the regulation of cilia length, architecture and stability. Next, in human cell lines, the authors found that overexpressed KIF7 forms homodimers and colocalizes to microtubule bundles. The association with microtubules was mediated by the motor domain, which is in agreement with the finding that this domain is required for the proper localization of KIF7 in cilia. Interestingly, the authors found that KIF7, unlike most kinesins, did not diffuse or directionally move along microtubules in vitro. The authors went on to test whether KIF7 regulates microtubule growth by altering tubulin polymerization dynamics. Using a dynamic microtubule assay, they found that addition of the KIF7 motor domain
promoted microtubule shrinkage (catastrophe) and preferentially inhibited microtubule growth at the plus ends. Microtubule growth was not inhibited in the presence of a non-hydrolysable ATP analogue, which suggests that ATP hydrolysis is required for KIF7‑mediated regulation of microtubule plus-end dynamics. Moreover, time-lapse imaging revealed that the motor protein associated with GTP-bound tubulin at the growing plus end of microtubules during the growing phase and dissociated at the onset of catastrophe. Thus, KIF7 destabilizes the GTP-bound tubulin cap to induce catastrophe and limit microtubule growth. Finally, the authors showed that KIF7 was not required for intra flagellar transport or trafficking of components of the HH signalling pathway into cilia; however, KIF7 was crucial for the generation of a compartment at the cilium tip that ensured the proper localization and regulation of HH signalling. In summary, this study shows that KIF7 regulates tubulin dynamics to control both cilia structure and HH signalling. Andrea Du Toit ORIGINAL RESEARCH PAPER He, M. et al. The kinesin‑4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nature Cell Biol. http://dx.doi. org/10.1038/ncb2988 (2014)
ImageSource
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
VOLUME 15 | AUGUST 2014 © 2014 Macmillan Publishers Limited. All rights reserved
Copyright of Nature Reviews Molecular Cell Biology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
