The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-lasting questions about this pathway are how dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells, and how the resistance-nodulation-division transporter Dispatched (Disp) regulates this process. Here we show that Disp inactivation in Shh expressing cells specifically impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding. Shh shedding from Disp-deficient cells was restored by pharmacological membrane cholesterol extraction and by overexpressed transgenic Disp or structurally related Patched (Ptc, a putative cholesterol transporter). These data suggest that Disp regulates physiological Shh function via controlled cell surface shedding and that molecular mechanisms shared by Disp and Ptc exercise such sheddase control.

中文翻译：

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保守的胆固醇相关活动的派遣驱动声波刺猬从细胞膜脱落

声波刺猬（Shh）途径控制出生后的胚胎发育和组织稳态。关于该途径的长期问题是，如何从生产细胞中释放出与血脂膜紧密相关的双脂膜Shh配体，从而向远处的靶细胞发出信号，以及抗性-结节-分裂转运蛋白Dispatched（Disp）如何调节这一过程。在这里，我们显示在Shh表达细胞中Disp失活会特别破坏蛋白水解Shh从其脂化末端肽的释放，此过程称为胞外域脱落。通过药理膜胆固醇提取和过表达的转基因Disp或与结构相关的Patched（Ptc，一种假定的胆固醇转运蛋白）可以恢复Disp缺陷细胞中的Shh脱落。