Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 15 September 2009
Vol. 2, Issue 88, p. ra55
[DOI: 10.1126/scisignal.2000304]


Differential Interactions of FGFs with Heparan Sulfate Control Gradient Formation and Branching Morphogenesis

Helen P. Makarenkova1,2*{dagger}, Matthew P. Hoffman3*, Andrew Beenken4, Anna V. Eliseenkova4, Robyn Meech2,5, Cindy Tsau1, Vaishali N. Patel3, Richard A. Lang6, and Moosa Mohammadi4*

1 The Neurobiology Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
2 The Neurosciences Institute, San Diego, CA 92121, USA.
3 Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
4 Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
5 Department of Clinical Pharmacology, Flinders University, Bedford Park, South Australia 5042, Australia.
6 The Visual Systems Group, Department of Ophthalmology and Division of Developmental Biology, Children’s Hospital Research Foundation, Cincinnati, OH 45229, USA.

* These authors contributed equally to this work.

Abstract: The developmental activities of morphogens depend on the gradients that they form in the extracellular matrix. Here, we show that differences in the binding of fibroblast growth factor 7 (FGF7) and FGF10 to heparan sulfate (HS) underlie the formation of different gradients that dictate distinct activities during branching morphogenesis. Reducing the binding affinity of FGF10 for HS by mutating a single residue in its HS-binding pocket converted FGF10 into a functional mimic of FGF7 with respect to gradient formation and regulation of branching morphogenesis. In particular, the mutant form of FGF10 caused lacrimal and salivary gland epithelium buds to branch rather than to elongate. In contrast, mutations that reduced the affinity of the FGF10 for its receptor affected the extent, but not the nature, of the response. Our data may provide a general model for understanding how binding to HS regulates other morphogenetic gradients.

{dagger} To whom correspondence should be addressed. E-mail: hmakarenk{at}

Citation: H. P. Makarenkova, M. P. Hoffman, A. Beenken, A. V. Eliseenkova, R. Meech, C. Tsau, V. N. Patel, R. A. Lang, M. Mohammadi, Differential Interactions of FGFs with Heparan Sulfate Control Gradient Formation and Branching Morphogenesis. Sci. Signal. 2, ra55 (2009).

Read the Full Text

The control of branching morphogenesis.
D. Iber and D. Menshykau (2013)
Open Bio 3, 130088
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of Fibroblast Growth Factor Signaling in Physiology and Pathology.
A. A. Belov and M. Mohammadi (2013)
Cold Spring Harb Perspect Biol 5, a015958
   Abstract »    Full Text »    PDF »
Morphogen transport.
P. Muller, K. W. Rogers, S. R. Yu, M. Brand, and A. F. Schier (2013)
Development 140, 1621-1638
   Abstract »    Full Text »    PDF »
Diversification of the Structural Determinants of Fibroblast Growth Factor-Heparin Interactions: IMPLICATIONS FOR BINDING SPECIFICITY.
R. Xu, A. Ori, T. R. Rudd, K. A. Uniewicz, Y. A. Ahmed, S. E. Guimond, M. A. Skidmore, G. Siligardi, E. A. Yates, and D. G. Fernig (2012)
J. Biol. Chem. 287, 40061-40073
   Abstract »    Full Text »    PDF »
Conversion of a Paracrine Fibroblast Growth Factor into an Endocrine Fibroblast Growth Factor.
R. Goetz, M. Ohnishi, S. Kir, H. Kurosu, L. Wang, J. Pastor, J. Ma, W. Gai, M. Kuro-o, M. S. Razzaque, et al. (2012)
J. Biol. Chem. 287, 29134-29146
   Abstract »    Full Text »    PDF »
Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development.
X. Qu, Y. Pan, C. Carbe, A. Powers, K. Grobe, and X. Zhang (2012)
Development 139, 2730-2739
   Abstract »    Full Text »    PDF »
Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands.
R. Goetz, M. Ohnishi, X. Ding, H. Kurosu, L. Wang, J. Akiyoshi, J. Ma, W. Gai, Y. Sidis, N. Pitteloud, et al. (2012)
Mol. Cell. Biol. 32, 1944-1954
   Abstract »    Full Text »    PDF »
Extracellular Matrix in Development: Insights from Mechanisms Conserved between Invertebrates and Vertebrates.
N. H. Brown (2011)
Cold Spring Harb Perspect Biol 3, a005082
   Abstract »    Full Text »    PDF »
Barx2 and Fgf10 regulate ocular glands branching morphogenesis by controlling extracellular matrix remodeling.
C. Tsau, M. Ito, A. Gromova, M. P. Hoffman, R. Meech, and H. P. Makarenkova (2011)
Development 138, 3307-3317
   Abstract »    Full Text »    PDF »
Lacrimal Gland Development and Fgf10-Fgfr2b Signaling Are Controlled by 2-O- and 6-O-sulfated Heparan Sulfate.
X. Qu, C. Carbe, C. Tao, A. Powers, R. Lawrence, T. H. van Kuppevelt, W. V. Cardoso, K. Grobe, J. D. Esko, and X. Zhang (2011)
J. Biol. Chem. 286, 14435-14444
   Abstract »    Full Text »    PDF »
Influence of Heparin Mimetics on Assembly of the FGF{middle dot}FGFR4 Signaling Complex.
K. Saxena, U. Schieborr, O. Anderka, E. Duchardt-Ferner, B. Elshorst, S. L. Gande, J. Janzon, D. Kudlinzki, S. Sreeramulu, M. K. Dreyer, et al. (2010)
J. Biol. Chem. 285, 26628-26640
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882