The key is the binding partner: the range of morphogen-mediated signaling is regulated by the antagonists and two different types of heparan sulfate

Morphogens (e.g. Wnt and BMP) are secreted from source cells and diffuse in the extracellular space, making a gradient that organizes embryonic development, regeneration, and diseases. However, how morphogen distribution and signalling range is regulated was poorly understood. My colleagues have previously shown that Wnt distribution range was expanded by the secreted antagonists (Mii & Taira, 2009). Surprisingly, not only the protein distribution range, but also signal activation range were expanded by the antagonists (“Antagonists” promoted signalling!). To understand this phenomenon, we focused on an extracellular matrix, heparan sulfate, which have been known to regulate morphogen distribution. We newly identified two types of heparan sulfate (HS) clusters: N-sulfo-rich HS (NS) and N-acetyl-rich HS (NAc), which differently modulate Wnt distribution and signalling. NS clusters accumulate Wnt proteins to transduce its signal and make the Wnt distribution shorter mediating endocytosis of Wnt. In contrast, NAc clusters accumulate Frzb (an antagonist of Wnt). Frzb changes Wnt localisation from NS to NAc clusters to prevent Wnt endocytosis, making the Wnt distribution and signaling range broader (Mii and Yamamoto et al., 2017). We have also revealed that this mechanism is applicable to another morphogen, BMP (Yamamoto et al., unpublished). This suggests that the NAc/NS cluster system could be the general molecular basis of morphogen distribution and signalling ranges.

 

*Mii Y, *Yamamoto T (*co-first author), Takada R, Mizumoto S, Matsuyama M, Yamada S, Takada S, Taira M (2017). Roles of two types of heparan sulfate clusters in Wnt distribution and signaling in Xenopus. Nat Commun. 2017 Dec 7;8(1):1973. doi: 10.1038/s41467-017-02076-0.