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Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation

Fanxin Long, Xiaoyan M. Zhang^*, Seth Karp, Yingzi Yang and Andrew P. McMahon

Harvard University, Department of Molecular and Cellular Biology, Cambridge, MA 02138, USA
^* Present address: Curis, 45 Moulton Street, Cambridge, MA 02138, USA
Present address: Department of Surgery, Brigham and Womern’s Hospital, 75 Francis St, Boston, MA 02115, USA
Present address: Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA

Author for correspondence (e-mail: amcmahon{at}mcb.harvard.edu)

Accepted September 22, 2001

Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone development. Smoothened (Smo) is a transmembrane protein that transduces all Hh signals. In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes. Animals generated by this means develop shorter long bones when compared to wild-type littermates. In contrast to Ihh mutants (Ihhⁿ/Ihhⁿ), chondrocyte differentiation proceeds normally. However, like Ihhⁿ/Ihhⁿ mice, proliferation of chondrocytes is reduced by about 50%, supporting a direct role for Ihh in the regulation of chondrocyte proliferation. Moreover, by overexpressing either Ihh or a constitutively active Smo allele (Smo*) specifically in the cartilage using the bigenic UAS-Gal4 system, we demonstrate that activation of the Ihh signaling pathway is sufficient to promote chondrocyte proliferation. Finally, expression of cyclin D1 is markedly downregulated when either Ihh or Smo activity is removed from chondrocytes, indicating that Ihh regulates chondrocyte proliferation at least in part by modulating the transcription of cyclin D1. Taken together, the present study establishes Ihh as a key mitogen in the endochondral skeleton.

Key words: Ihh, Smo, Chondrocyte proliferation, Cyclin D1, Mouse

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