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J. Biol. Chem., Vol. 283, Issue 14, 9308-9317, April 4, 2008

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Specific Heparan Sulfate Structures Modulate FGF10-mediated Submandibular Gland Epithelial Morphogenesis and Differentiation^*

Vaishali N. Patel, Karen M. Likar, Simona Zisman-Rozen^¶, Samuel N. Cowherd, Keyonica S. Lassiter, Ifat Sher^¶, Edwin A. Yates^||, Jeremy E. Turnbull^||, Dina Ron^¶, and Matthew P. Hoffman¹

From the Matrix and Morphogenesis Unit, Laboratory of Cell and Developmental Biology, NIDCR, National Institutes of Health, DHHS, Bethesda, Maryland 20892, the Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, Maryland 20814, the ^¶Biology Department, Technion, Haifa 32000, Israel, and the ^||School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom

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.

Received for publication, December 7, 2007 , and in revised form, January 14, 2008.

^* This work was supported by the Intramural Research Program of the NIDCR, National Institutes of Health, and by grants from the DKFZ, Israel Science Foundation, and Ministry of Health (to D. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: LCDB, NIDCR, National Institutes of Health, Bldg. 30/Rm. 430, 30 Convent Dr., MSC 4370, Bethesda, MD 20892-4370. Fax: 301-402-0897; E-mail: mhoffman{at}mail.nih.gov.

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