Specific heparan sulfate structures modulate FGF10-mediated submandibular gland epithelial morphogenesis and...

Area of Science:

• Developmental Biology
• Glycobiology
• Cell Signaling

Background:

• Fibroblast Growth Factor 10 (FGF10) is crucial for mouse submandibular gland (SMG) branching morphogenesis.
• Heparan sulfate (HS) binding enhances FGF10 affinity for FGFR2b, forming a ternary complex that drives proliferation and epithelial morphogenesis.
• Understanding HS structure-function relationships is key to deciphering FGF10 signaling in development.

Purpose of the Study:

• To investigate the specific HS structural requirements for FGF10-mediated proliferation using HS-deficient cells.
• To determine the HS structural basis for FGF10-driven epithelial morphogenesis in primary SMG epithelia.

Main Methods:

• Utilized HS-deficient BaF3/FGFR2b cells for proliferation studies.
• Employed primary mouse SMG epithelia for morphogenesis investigations.
• Analyzed FGF10-mediated events using defined heparin decasaccharide libraries and gene expression analysis.

Main Results:

• Maximal proliferation in BaF3/FGFR2b cells required heparin of at least 10 saccharides with 6-O-, 2-O-, and N-sulfates.
• In SMG epithelia, HS promoted proliferation and end bud expansion.
• Specific HS structures differentially regulated morphogenesis: 2-O-sulfation with N- or 6-O-sulfation induced end bud expansion, while 6-O-sulfation alone promoted duct elongation.

Conclusions:

• HS size and sulfation patterns precisely modulate FGF10-mediated proliferation, duct elongation, end bud expansion, and differentiation.
• These findings provide mechanistic insights into how HS localization influences FGF10-driven morphogenesis and differentiation during development.