FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis
Affiliation:
1. Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110 USA.
Abstract
Fibroblast growth factors (FGFs) are signals from the apical ectodermal ridge (AER) that are essential for limb pattern formation along the proximodistal (PD) axis. However, how patterning along the PD axis is regulated by AER-FGF signals remains controversial. To further explore the molecular mechanism of FGF functions during limb development, we conditionally inactivated fgf receptor 2 (Fgfr2) in the mouse AER to terminate all AER functions; for comparison, we inactivated both Fgfr1 and Fgfr2 in limb mesenchyme to block mesenchymal AER-FGF signaling. We also re-examined published data in which Fgf4 and Fgf8 were inactivated in the AER. We conclude that limb skeletal phenotypes resulting from loss of AER-FGF signals cannot simply be a consequence of excessive mesenchymal cell death, as suggested by previous studies, but also must be a consequence of reduced mesenchymal proliferation and a failure of mesenchymal differentiation, which occur following loss of both Fgf4 and Fgf8. We further conclude that chondrogenic primordia formation,marked by initial Sox9 expression in limb mesenchyme, is an essential component of the PD patterning process and that a key role for AER-FGF signaling is to facilitate SOX9 function and to ensure progressive establishment of chondrogenic primordia along the PD axis.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference48 articles.
1. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. and de Crombrugghe, B. (2002). The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev.16,2813-2828. 2. Akiyama, H., Kim, J. E., Nakashima, K., Balmes, G., Iwai, N.,Deng, J. M., Zhang, Z., Martin, J. F., Behringer, R. R., Nakamura, T. et al. (2005). Osteochondroprogenitor cells are derived from Sox9 expressing precursors. Proc. Natl. Acad. Sci. USA102,14665-14670. 3. Barna, M., Pandolfi, P. P. and Niswander, L.(2005). Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature436,277-281. 4. Barrow, J. R., Thomas, K. R., Boussadia-Zahui, O., Moore, R.,Kemler, R., Capecchi, M. R. and McMahon, A. P. (2003). Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev.17,394-409. 5. Bi, W., Huang, W., Whitworth, D. J., Deng, J. M., Zhang, Z.,Behringer, R. R. and de Crombrugghe, B. (2001). Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Natl. Acad. Sci. USA98,6698-6703.
Cited by
112 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|