Proteolytic processing of palmitoylated Hedgehog peptides specifies the 3-4 intervein region of the Drosophila wing

Cell fate determination during development often requires morphogen transport from producing to distant responding cells. Hedgehog (Hh) morphogens present a challenge to this concept, as all Hhs are synthesized as terminally lipidated molecules that form insoluble clusters at the surface of producing cells. While several proposed Hh transport modes tie directly into these unusual properties, the crucial step of Hh relay from producing cells to receptors on remote responding cells remains unresolved. Using wing development in Drosophila melanogaster as a model, we show that Hh relay and direct patterning of the 3-4 intervein region strictly depend on proteolytic removal of lipidated N-terminal membrane anchors. Site-directed modification of the N-terminal Hh processing site selectively eliminated the entire 3-4 intervein region, and additional targeted removal of N-palmitate restored its formation. Hence, palmitoylated membrane anchors restrict morphogen spread until site-specific proces...

发育过程中的细胞命运决定通常依赖于形态发生因子从产生细胞向远端响应细胞的转运。音猬因子(Hedgehog, Hh)对这一认知提出了挑战：所有Hh蛋白均合成为末端脂修饰的分子，并在产生细胞表面形成不溶性簇集物。尽管已提出多种与该异常特性直接相关的Hh转运模型，但从产生细胞到远端响应细胞表面受体的Hh信号传递关键步骤仍未阐明。本研究以黑腹果蝇(Drosophila melanogaster)的翅发育为模型，证实Hh信号传递与3-4翅脉间区的直接模式建成严格依赖于脂修饰N端膜锚定结构的蛋白水解去除。对Hh的N端加工位点进行定点修饰可选择性消除整个3-4翅脉间区，而额外靶向去除N-棕榈酰化修饰则可恢复该区域的形成。由此可见，棕榈酰化膜锚定结构会限制形态发生因子的扩散，直至位点特异性加工...