Hif-1alpha regulates differentiation of limb bud mesenchyme and joint development.
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.
Provot
Sylvain
S
Endocrine Unit, Department of Medicine, Massachusetts General Hospital-Harvard Medical School, Boston, MA 02114, USA.
Zinyk
Dawn
D
Gunes
Yasemin
Y
Kathri
Richa
R
Le
Quynh
Q
Kronenberg
Henry M
HM
Johnson
Randall S
RS
Longaker
Michael T
MT
Giaccia
Amato J
AJ
Schipani
Ernestina
E
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D020219:Chondrogenesis / Q000502:physiology*; D005260:Female; D006614:Hindlimb / Q000166:cytology / Q000196:embryology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000378:metabolism*; D007596:Joints / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit