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Published online April 30, 2007
doi:10.1083/jcb.200612023
The Journal of Cell Biology, Vol. 177, No. 3, 451-464
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Provot et al.
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Article

 Hif-1{alpha} regulates differentiation of limb bud mesenchyme and joint development

Sylvain Provot1, Dawn Zinyk2, Yasemin Gunes1, Richa Kathri1, Quynh Le2, Henry M. Kronenberg1, Randall S. Johnson3, Michael T. Longaker2, Amato J. Giaccia2, and Ernestina Schipani1

1 Endocrine Unit, Department of Medicine, Massachusetts General Hospital-Harvard Medical School, Boston, MA 02114
2 Division of Cancer and Radiation Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305
3 Molecular Biology Section, University of California, San Diego, La Jolla, CA 92093

Correspondence to Amato J. Giaccia: Giaccia{at}stanford.edu

Recent evidence suggests that low oxygen tension (hypoxia) may control fetal development and differentiation. A crucial mediator of the adaptive response of cells to hypoxia is the transcription factor Hif-1{alpha}. In this study, we provide evidence that mesenchymal condensations that give origin to endochondral bones are hypoxic during fetal development, and we demonstrate that Hif-1{alpha} is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations. To investigate the role of Hif-1{alpha} in mesenchymal condensations and in early chondrogenesis, we conditionally inactivated Hif-1{alpha} in limb bud mesenchyme using a Prx1 promoter-driven Cre transgenic mouse. Conditional knockout of Hif-1{alpha} in limb bud mesenchyme does not impair mesenchyme condensation, but alters the formation of the cartilaginous primordia. Late hypertrophic differentiation is also affected as a result of the delay in early chondrogenesis. In addition, mutant mice show a striking impairment of joint development. Our study demonstrates a crucial, and previously unrecognized, role of Hif-1{alpha} in early chondrogenesis and joint formation.

S. Provot and D. Zinyk contributed equally to this paper.

Abbreviations used in this paper: CKO, conditional knockout; E, embryonic day; Hif-1{alpha}, hypoxia-inducible factor 1{alpha}; HRE, hypoxia response element; H&E, hematoxylin and eosin; Ihh, Indian hedgehog; P, postnatal day; p4haI, prolyl-4-hydroxylase {alpha} (I); PNA, Peanut agglutinin; VEGFR2, VEGF-receptor2.


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