Developmental Biology

The Duality of Kif7

Science Signaling  16 Aug 2011:
Vol. 4, Issue 186, pp. ec225
DOI: 10.1126/scisignal.4186ec225

Hedgehog (Hh) signaling plays a pivotal role in growth, development, and homeostasis. Primary cilia are of central importance for Hh signal transduction, and dynamic trafficking of several hedgehog signaling components, including the kinesin motor protein Kif7 and the Gli transcription factors, is required for appropriate signaling. Kif7 interacts with Gli proteins and appears to affect Hh signaling both positively and negatively, but the mechanism by which Kif7 influences Hh signaling has remained incomplete. Hsu et al. report that Kif7 restricts the ability of Suppressor of fused (Sufu) to bind to and repress the activity of the Gli family of transcription factors in chondrocytes. Signaling from the Hh ligand Indian hedgehog (Ihh) controls the balance between proliferation and differentiation of chondrocytes in the growth plates of developing mouse embryos. Chondrocyte-specific loss of Sufu promoted proliferation and inhibited differentiation (ossification) of these bone-building cells similarly to, but more weakly than, loss of the Hh receptor Ptch1. Loss of Kif7 in chondrocytes, on the other hand, reduced proliferation, stimulated differentiation, and promoted expression of Hh target genes, indicating that Kif7 promoted Ihh signaling in this context. The abundance of Sufu protein, but not transcripts, was increased in Kif7-deficient chondrocytes, suggesting that Kif7 inhibited turnover of Sufu. Removing one copy of Sufu rescued the Kif7 growth plate phenotype. In proliferating wild-type chondrocytes, Kif7 was present at the tips of primary cilia, and Sufu was mostly present at basal bodies with little Sufu, Gli2, or Gli3 in the cilium. Whereas Kif7 localization to the ciliary tip was unaffected in Sufu mutant chondrocytes, Sufu-Gli complexes accumulated in the tips of cilia in Kif7-deficient chondrocytes. Genetic interaction experiments indicated that Kif7 inhibited Ihh signaling in chondrocytes in the absence of Sufu, likely by preventing processing of Gli proteins in the cilium. The authors thus propose that Kif7 reduces the ability of Sufu to repress Gli proteins, thereby promoting Ihh signaling during chondrocyte development, but also inhibits Gli activity and therefore Ihh signaling through a Sufu-independent mechanism.

S.-H. C. Hsu, X. Zhang, C. Yu, Z. J. Li, J. S. Wunder, C.-C. Hui, B. A. Alman, Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. Development 138, 3791–3801 (2011). [Abstract] [Full Text]