Title:
Heparan sulfate chains and local reception of FGF signaling

Isao Matsuo,
Department of Molecular Embryology
Osaka Medical Center and Research Institute for Maternal and Child Health
Osaka Prefectural Hospital Organization

Abstract:
Spatio-temporal signaling activation of diffusible growth factors is one of the key processes controlling complex morphogenesis in mammalian embryos. Heparan sulfate (HS) proteoglycans consist of HS chains and a core protein, which reside in the cell surface or extracellular matrix, and modulate the activity of multiple growth factors on the cell surface and extracellular matrix. However, it remains unclear how the HS chains control the movement and reception of growth factors into targeted receiving cells during mammalian morphogenetic processes. In current study, we found that HS-deficient Ext2 null mutant mouse embryos fail to respond to fibroblast growth factor (FGF) signaling. Marker expression analyses revealed that cell surface-tethered HS chains are crucial for local retention of FGF4 and FGF8 ligands in the extraembryonic ectoderm. Fine chimeric studies with single-cell resolution and expression studies with specific inhibitors for HS movement demonstrated that proteolytic cleavage of HS chains can spread FGF signaling to adjacent cells within a short distance. Given that 22 FGF ligands, 4 FGF receptors and 12 cell surface core proteins are redundantly expressed during mammalian morphogenetic processes, we propose that spatio-temporal expression of cell surface-tethered HS chains regulate the local reception of FGF signaling in the right place at the right time in mammalian embryos.

References:
Shimokawa K, Kimura-Yoshida C, Nagai N, Mukai K, Matsubara K, Watanabe H, Matsuda Y, Mochida K, and Matsuo I.
Cell surface heparan sulfate chains regulate local reception of FGF signaling in the mouse embryo.
Developmental Cell 21: 257-272 (2011).