Wnt signaling is essential for embryonic development and tissue homeostasis. So far, little is known about the importance and functional relevance of the different regions in WNT proteins including regions in their C-terminus identified as hairpin and linker. However, it was shown that the C-terminus of WNT7A comprising the linker and the hairpin region is sufficient to elicit signaling. Here, we demonstrate that actually the hairpin region of WNT7A in its C-terminus is fully sufficient to induce non-canonical signaling in myogenic cells while the linker region alone did not show biological activity. Of note, all known non-canonical signaling branches of WNT7A signaling in skeletal muscle were activated by the hairpin region of WNT7A thereby inducing hypertrophy in myotubes, symmetric expansion of satellite stem cells and migration of myoblasts. Furthermore, we demonstrate that the linker region in the C-terminus of WNT7A binds to the FZD7 receptor while it does not activate non-canonical Wnt signaling. However, the hairpin and the linker region of WNT7A can activate canonical Wnt signaling independent of each other suggesting that specificity of downstream signaling might be depending on those specific regions in the C-terminus.

Wnt 信号对于胚胎发育和组织稳态至关重要。到目前为止，人们对 WNT 蛋白中不同区域的重要性和功能相关性知之甚少，包括其 C 末端被确定为发夹和接头的区域。然而，显示包含接头和发夹区域的 WNT7A 的 C 末端足以引发信号传导。在这里，我们证明实际上 WNT7A C 末端的发夹区域足以在生肌细胞中诱导非规范信号传导，而单独的接头区域没有显示出生物活性。值得注意的是，骨骼肌中 WNT7A 信号的所有已知非经典信号分支都被 WNT7A 的发夹区域激活，从而诱导肌管肥大、卫星干细胞的对称扩张和成肌细胞的迁移。此外，我们证明 WNT7A C 末端的接头区域与 FZD7 受体结合，同时它不会激活非经典 Wnt 信号传导。然而，WNT7A 的发夹和连接子区域可以激活彼此独立的经典 Wnt 信号，这表明下游信号的特异性可能取决于 C 末端的那些特定区域。