The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
HIF1α regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis
Abstract
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 1α (HIF1α) in mouse limb bud mesenchyme. Developmental analysis of Hif1α-depleted limbs revealed abnormal cartilage and joint formation in the autopod,suggesting that HIF1α is part of a mechanism that regulates the differentiation of hypoxic prechondrogenic cells. Dramatically reduced cartilage formation in Hif1α-depleted micromass culture cells under hypoxia provided further support for the regulatory role of HIF1αin chondrogenesis. Reduced expression of Sox9, a key regulator of chondrocyte differentiation, followed by reduction of Sox6, collagen type II and aggrecan in Hif1α-depleted limbs raised the possibility that HIF1α regulation of Sox9 is necessary under hypoxic conditions for differentiation of prechondrogenic cells to chondrocytes. To study this possibility, we targeted Hif1αexpression in micromass cultures. Under hypoxic conditions, Sox9expression was increased twofold relative to its expression in normoxic condition; this increment was lost in the Hif1α-depleted cells. Chromatin immunoprecipitation demonstrated direct binding of HIF1α to the Sox9 promoter, thus supporting direct regulation of HIF1αon Sox9 expression. This work establishes for the first time HIF1α as a key component in the genetic program that regulates chondrogenesis by regulating Sox9 expression in hypoxic prechondrogenic cells.
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Citations
Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
Forsythe, J. A., Jiang, B.-H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., & Semenza, G. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4604 · Cited by 3,981
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · cited 1×
“It then binds to HIF1 and enhances the transcription of genes that are involved in glucose metabolism, angiogenesis, and cell survival (Schofield and Ratcliffe, 2004; Semenza, 2003).”
BackgroundAkiyama, H., Chaboissier, M.-C., Martin, J. F., Schedl, A., & de Crombrugghe, B. (2002) · Genes & Development · doi:10.1101/gad.1017802 · Cited by 1,721
Hypoxia requires Notch signaling to maintain the undifferentiated cell state
Gustafsson, M. V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J. L., Poellinger, L., Lendahl, U., & Bondesson, M. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.09.010 · Cited by 1,109
Hypoxia-inducible factor 1: master regulator of O2 homeostasis
Semenza, G. L. (1998) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(98)80016-6 · Cited by 1,092
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Medici, D., Shore, E. M., Lounev, V. Y., Kaplan, F. S., Kalluri, R., & Olsen, B. R. (2010) · Nature Medicine · doi:10.1038/nm.2252 · Cited by 678
The Role of Hypoxia in Development of the Mammalian Embryo
Dunwoodie, S. L. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.11.008 · Cited by 651
Saito, T., Fukai, A., Mabuchi, A., Ikeda, T., Yano, F., Ohba, S., Nishida, N., Akune, T., Yoshimura, N., Nakagawa, T., et al. (2010) · Nature Medicine · doi:10.1038/nm.2146 · Cited by 532
Targeted Disruption of Hotair Leads to Homeotic Transformation and Gene Derepression
Li, L., Liu, B., Wapinski, O. L., Tsai, M.-C., Qu, K., Zhang, J., Carlson, J. C., Lin, M., Fang, F., Gupta, R. A., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.09.003 · Cited by 317
Control of chondrogenesis by the transcription factor Sox9
Akiyama, H. (2008) · Modern Rheumatology · doi:10.1007/s10165-008-0048-x · Cited by 285
SOX9 in cartilage development and disease
Lefebvre, V., Angelozzi, M., & Haseeb, A. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.07.008 · Cited by 268
Role of HIF‐1α in skeletal development
Wan, C., Shao, J., Gilbert, S. R., Riddle, R. C., Long, F., Johnson, R. S., Schipani, E., & Clemens, T. L. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05238.x · Cited by 173
Self-citationBoyette, L. B., Creasey, O. A., Guzik, L., Lozito, T., & Tuan, R. S. (2014) · Stem Cells Translational Medicine · doi:10.5966/sctm.2013-0079 · Cited by 121
A Central Role for Hypoxic Signaling in Cartilage, Bone, and Hematopoiesis
Rankin, E. B., Giaccia, A. J., & Schipani, E. (2011) · Current Osteoporosis Reports · doi:10.1007/s11914-011-0047-2 · Cited by 93
The Role of Hypoxia in Stem Cell Potency and Differentiation
Hawkins, K. E., Sharp, T. V., & McKay, T. R. (2013) · Regenerative Medicine · doi:10.2217/rme.13.71 · Cited by 87
Defining the role of oxygen tension in human neural progenitor fate
Xie, Y., Zhang, J., Lin, Y., Gaeta, X., Meng, X., Wisidagama, D. R. R., Cinkornpumin, J., Koehler, C. M., Malone, C. S., Teitell, M. A., et al. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.09.021 · Cited by 65
Metadata
- Authors
- Amarilio, R., Viukov, S. V., Sharir, A., Eshkar-Oren, I., Johnson, R. S., & Zelzer, E.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2007-11-01
- Volume
- 134
- Issue
- 21
- Pages
- 3917-3928
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2023060332
- Cited by
- 313
- References
- 8
- FWCI
- 8.69
- Type
- journal article
- Language
- en
- Open access
- closed
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