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First published online 3 October 2007
doi: 10.1242/dev.008441
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regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis
1 Department of Molecular Genetics, Weizmann Institute of Science, PO Box 26,
Rehovot 76100, Israel.
2 Molecular Biology Section, Division of Biology, University of California, San
Diego, CA, USA.
* Author for correspondence (e-mail: eli.zelzer{at}weizmann.ac.il)
Accepted 21 August 2007
During early stages of limb development, the vasculature is subjected to
extensive remodeling that leaves the prechondrogenic condensation avascular
and, as we demonstrate hereafter, hypoxic. Numerous studies on a variety of
cell types have reported that hypoxia has an inhibitory effect on cell
differentiation. In order to investigate the mechanism that supports
chondrocyte differentiation under hypoxic conditions, we inactivated the
transcription factor hypoxia-inducible factor 1
(HIF1) in mouse
limb bud mesenchyme. Developmental analysis of Hif1-depleted
limbs revealed abnormal cartilage and joint formation in the autopod,
suggesting that HIF1 is part of a mechanism that regulates the
differentiation of hypoxic prechondrogenic cells. Dramatically reduced
cartilage formation in Hif1-depleted micromass culture cells
under hypoxia provided further support for the regulatory role of HIF1
in chondrogenesis. Reduced expression of Sox9, a key regulator of
chondrocyte differentiation, followed by reduction of Sox6, collagen
type II and aggrecan in Hif1-depleted limbs raised the
possibility that HIF1 regulation of Sox9 is necessary under
hypoxic conditions for differentiation of prechondrogenic cells to
chondrocytes. To study this possibility, we targeted Hif1
expression in micromass cultures. Under hypoxic conditions, Sox9
expression was increased twofold relative to its expression in normoxic
condition; this increment was lost in the Hif1-depleted cells.
Chromatin immunoprecipitation demonstrated direct binding of HIF1 to
the Sox9 promoter, thus supporting direct regulation of HIF1
on Sox9 expression. This work establishes for the first time
HIF1 as a key component in the genetic program that regulates
chondrogenesis by regulating Sox9 expression in hypoxic
prechondrogenic cells.
Key words: Hypoxia, HIF1, HIF1, Mesenchymal condensation, Chondrocyte differentiation, Chondrogenesis, SOX9, Joint formation, Bone development, VEGF, GDF5, BMP, SOX5, SOX6
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