Abstract
FGF10, a heparan sulfate (HS)-binding growth factor, is required for branching morphogenesis of mouse submandibular glands (SMGs). HS increases the affinity of FGF10 for FGFR2b, which forms an FGF10.FGFR2b.HS ternary signaling complex, and results in diverse biological outcomes, including proliferation and epithelial morphogenesis. Defining the HS structures involved in specific FGF10-mediated events is critical to understand how HS modulates growth factor signaling in specific developmental contexts. We used HS-deficient BaF3/FGFR2b cells, which require exogenous HS to proliferate, to investigate the HS requirements for FGF10-mediated proliferation and primary SMG epithelia to investigate the structural requirements of HS for FGF10-mediated epithelial morphogenesis. In BaF3/FGFR2b cells, heparin with at least 10 saccharides and 6-O-, 2-O-, and N-sulfates were required for maximal proliferation. During FGF10-mediated SMG epithelial morphogenesis, HS increased proliferation and end bud expansion. Defined heparin decasaccharide libraries showed that 2-O-sulfation with either an N-or 6-O-sulfate induced end bud expansion, whereas decasaccharides with 6-O-sulfation alone induced duct elongation. End bud expansion resulted from increased FGFR1b signaling, with increased FGFR1b, Fgf1, and Spry1 as well as increased Aqp5 expression, a marker of end bud differentiation. Duct elongation was associated with expression of Cp2L1, a marker of developing ducts. Collectively, these findings show that the size and sulfate patterns of HS modulate specific FGF10-mediated events, such as proliferation, duct elongation, end bud expansion, and differentiation, and provide mechanistic insight as to how the developmental localization of specific HS structures in tissues influences FGF10-mediated morphogenesis and differentiation.
Highlights
FGF10, a heparan sulfate (HS)-binding growth factor, is required for branching morphogenesis of mouse submandibular glands (SMGs)
Epithelia cultured with FGF10 (200 ng/ml) and 0.5 g/ml heparin underwent extensive budding but no duct elongation (Fig. 3, B and C), and the morphogenic index was similar to epithelium cultured with no heparin, whereas HS, which has a lower overall and more heterogeneous pattern of sulfation, increased duct length and end bud width, resulting in increased morphogenesis compared with heparin
We analyzed the structural modifications of heparin that influence the biological activity of FGF10 bud (Fig. 6A), whereas FGFR2 is expressed throughout the using two complementary experimental systems: 1) BaF3 cells, epithelium
Summary
FGF10, a heparan sulfate (HS)-binding growth factor, is required for branching morphogenesis of mouse submandibular glands (SMGs). HS increases the affinity of FGF10 for FGFR2b, which forms an FGF101⁄7FGFR2b1⁄7HS ternary signaling complex, and results in diverse biological outcomes, including proliferation and epithelial morphogenesis. Duct elongation was associated with expression of Cp2L1, a marker of developing ducts These findings show that the size and sulfate patterns of HS modulate specific FGF10-mediated events, such as proliferation, duct elongation, end bud expansion, and differentiation, and provide mechanistic insight as to how the developmental localization of specific HS structures in tissues influences FGF10-mediated morphogenesis and differentiation. We have shown that FGFR2b signaling regulates SMG proliferation and morphogenesis, which are dependent on laminin-511 and 1 integrin signaling, which reciprocally regulate FGFR and Fgf expression [17, 18] Both FGF10 and FGF7 bind FGFR2b, but FGF10 mitogenic activity is more heparin-dependent than FGF7 [3, 19]. We proposed that heparanase-derived HS fragments might influence both the bioavailability and the bioactivity of FGF10, resulting in distinct morphogenic outcomes
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