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First published online 12 December 2007
doi: 10.1242/dev.014829

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Bud specific N-sulfation of heparan sulfate regulates Shp2-dependent FGF signaling during lacrimal gland induction

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
² Programs in Signal Transduction and Stem Cells and Regeneration, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
³ Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁴ Department of General Zoology and Genetics, Westfälische Wilhelms-Universität Münster, Schlossplatz 5, 48149 Münster, Germany.

^* Author for correspondence (e-mail: xz4{at}iupui.edu)

Accepted 26 October 2007

Preferential outgrowth of the bud cells forms the basis of branching morphogenesis. Here, we show that lacrimal gland development requires specific modification of heparan sulfates by Ndst genes at the tip of the lacrimal gland bud. Systemic and conditional knockout experiments demonstrate the tissue specific requirement of Ndst1 and Ndst2 in the lacrimal gland epithelial, but not mesenchymal, cells, and the functional importance of Ndst1 in Fgf10-Fgfr2b, but not of Fgf1-Fgfr2b, complex formation. Consistent with this, Fgf10-induced ectopic lacrimal gland budding in explant cultures is dependent upon Ndst gene dose, and epithelial deletion of Fgfr2 abolishes lacrimal gland budding, its specific modification of heparan sulfate and its phosphorylation of Shp2 (Ptpn11 - Mouse Genome Informatics). Finally, we show that genetic ablation of Ndst1, Fgfr2 or Shp2 disrupts ERK signaling in lacrimal gland budding. Given the evolutionarily conserved roles of these genes, the localized activation of the Ndst-Fgfr-Shp2 genetic cascade is probably a general regulatory mechanism of FGF signaling in branching morphogenesis.

Key words: HSPG, Ndst, FGF, ERK, Branching morphogenesis, Lacrimal gland, Ptpn11, Mouse

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