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Hif-1 alpha regulates differentiation of limb bud mesenchyme and joint development JOURNAL OF CELL BIOLOGY Provot, S., Zinyk, D., Gunes, Y., Kathri, R., Le, Q., Kronenberg, H. M., Johnson, R. S., Longaker, M. T., Giaccia, A. J., Schipani, E. 2007; 177 (3): 451-464

Abstract

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-1alpha. 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-1alpha is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations. To investigate the role of Hif-1alpha in mesenchymal condensations and in early chondrogenesis, we conditionally inactivated Hif-1alpha in limb bud mesenchyme using a Prx1 promoter-driven Cre transgenic mouse. Conditional knockout of Hif-1alpha 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-1alpha in early chondrogenesis and joint formation.

View details for DOI 10.1083/jcb.200612023

View details for Web of Science ID 000246580000009

View details for PubMedID 17470636

View details for PubMedCentralID PMC2064828