Data from: 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 processing switches membrane-bound Hh into bioactive forms with specific patterning functions.

发育过程中的细胞命运决定通常依赖于形态发生素（morphogen）从产生细胞向远端响应细胞的转运。刺猬因子（Hedgehog，Hh）对这一经典认知提出了挑战：所有Hh均被合成为末端经脂修饰的分子，会在产生细胞表面形成不溶性聚集簇。尽管已有多种Hh转运模型直接关联其上述特殊理化特性，但从产生细胞向远端响应细胞表面受体完成Hh信号传递这一关键步骤仍未得到解析。本研究以黑腹果蝇（Drosophila melanogaster）的翅膀发育为实验模型，证实Hh信号传递与3-4翅脉间区域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 N端加工位点进行定点修饰，会选择性消除整个3-4翅脉间区域；而额外靶向去除N-棕榈酰基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素的扩散，直至位点特异性加工将膜结合型Hh转化为具备特定模式建成功能的生物活性形式。