Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Development 138 (17): 3791-3801


RESEARCH ARTICLES

Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu

Shu-Hsuan C. Hsu1,2, Xiaoyun Zhang1, Chunying Yu1, Zhu Juan Li1,4, Jay S. Wunder3, Chi-Chung Hui1,4, and Benjamin A. Alman1,2,5,*

1 Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
2 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
3 Samuel Lunenfeld Research Institute and Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada.
4 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
5 Division of Orthopaedic Surgery and Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

* Author for correspondence (benjamin.alman{at}sickkids.ca)

Accepted for publication 28 June 2011.

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.

Key Words: ChondrogenesisIndian hedgehogGli transcription factorsMouse


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia.
G. L. Coles and K. G. Ackerman (2013)
PNAS 110, E1898-E1905
   Abstract »    Full Text »    PDF »
Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis.
Z. J. Li, E. Nieuwenhuis, W. Nien, X. Zhang, J. Zhang, V. Puviindran, B. J. Wainwright, P. C. W. Kim, and C.-c. Hui (2012)
Development 139, 4152-4161
   Abstract »    Full Text »    PDF »
Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome.
A. Putoux, S. Nampoothiri, N. Laurent, V. Cormier-Daire, P. L. Beales, A. Schinzel, D. Bartholdi, C. Alby, S. Thomas, N. Elkhartoufi, et al. (2012)
J. Med. Genet. 49, 713-720
   Abstract »    Full Text »    PDF »
Suppressor of Fused (Sufu) Mediates the Effect of Parathyroid Hormone-like Hormone (Pthlh) on Chondrocyte Differentiation in the Growth Plate.
S.-H. C. Hsu, X. Zhang, S. Cheng, J. S. Wunder, C.-C. Hui, and B. A. Alman (2012)
J. Biol. Chem. 287, 36222-36228
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882