Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, and The Graduate Program in Molecular and Developmental Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Development. 2010 Jun;137(12):2033-44. doi: 10.1242/dev.045740.
Hedgehog (Hh) acts as a morphogen in various developmental contexts to specify distinct cell fates in a concentration-dependent manner. Hh signaling is regulated by two conserved cell-surface proteins: Ig/fibronectin superfamily member Interference hedgehog (Ihog) and Dally-like (Dlp), a glypican that comprises a core protein and heparan sulfate glycosaminoglycan (GAG) chains. Here, we show in Drosophila that the Dlp core protein can interact with Hh and is essential for its function in Hh signaling. In wing discs, overexpression of Dlp increases short-range Hh signaling while reducing long-range signaling. By contrast, Ihog has biphasic activity in Hh signaling in cultured cells: low levels of Ihog increase Hh signaling, whereas high levels decrease it. In wing discs, overexpression of Ihog represses high-threshold targets, while extending the range of low-threshold targets, thus showing opposite effects to Dlp. We further show that Ihog and its family member Boi are required to maintain Hh on the cell surface. Finally, Ihog and Dlp have complementary expression patterns in discs. These data led us to propose that Dlp acts as a signaling co-receptor. However, Ihog might not act as a classic co-receptor; rather, it may act as an exchange factor by retaining Hh on the cell surface, but also compete with the receptor for Hh binding.
刺猬 (Hh) 在各种发育环境中充当形态发生素，以浓度依赖的方式指定不同的细胞命运。Hh 信号受两种保守的细胞表面蛋白调节：免疫球蛋白/纤维连接蛋白超家族成员干扰刺猬 (Ihog) 和 Dally-like (Dlp)，Dally-like 是一种糖蛋白，由核心蛋白和肝素硫酸盐糖胺聚糖 (GAG) 链组成。在这里，我们在果蝇中表明，Dlp 核心蛋白可以与 Hh 相互作用，并且对于其在 Hh 信号转导中的功能是必需的。在翅膀盘中，Dlp 的过表达增加了短程 Hh 信号，同时减少了长程信号。相比之下，Ihog 在培养细胞中的 Hh 信号中具有两相活性：低水平的 Ihog 增加 Hh 信号，而高水平的 Ihog 则降低其信号。在翅膀盘中，Ihog 的过表达抑制高阈值靶标，同时扩展低阈值靶标的范围，因此与 Dlp 的作用相反。我们进一步表明，Ihog 和其家族成员 Boi 是维持细胞表面 Hh 的必需条件。最后，Ihog 和 Dlp 在盘片中具有互补的表达模式。这些数据使我们提出 Dlp 作为信号共受体发挥作用。然而，Ihog 可能不作为经典的共受体起作用；相反，它可能作为一种交换因子，通过保留细胞表面上的 Hh 起作用，但也与受体竞争 Hh 结合。
