Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road Parkville Victoria 3052, Australia.
Development. 2012 Sep;139(17):3168-79. doi: 10.1242/dev.078402.
During development, secreted morphogens, such as Hedgehog (Hh), control cell fate and proliferation. Precise sensing of morphogen levels and dynamic cellular responses are required for morphogen-directed morphogenesis, yet the molecular mechanisms responsible are poorly understood. Several recent studies have suggested the involvement of a multi-protein Hh reception complex, and have hinted at an understated complexity in Hh sensing at the cell surface. We show here that the expression of the proteoglycan Dally in Hh-receiving cells in Drosophila is necessary for high but not low level pathway activity, independent of its requirement in Hh-producing cells. We demonstrate that Dally is necessary to sequester Hh at the cell surface and to promote Hh internalisation with its receptor. This internalisation depends on both the activity of the hydrolase Notum and the glycosyl-phosphatidyl-inositol (GPI) moiety of Dally, and indicates a departure from the role of the second glypican Dally-like in Hh signalling. Our data suggest that hydrolysis of the Dally-GPI by Notum provides a switch from low to high level signalling by promoting internalisation of the Hh-Patched ligand-receptor complex.
在发育过程中，分泌的形态发生素，如 Hedgehog（Hh），控制细胞命运和增殖。为了进行形态发生素指导的形态发生，需要精确感知形态发生素水平和动态细胞反应，但负责的分子机制知之甚少。最近的几项研究表明，存在一个多蛋白 Hh 受体复合物，并且暗示细胞表面 Hh 感应存在被低估的复杂性。我们在这里表明，果蝇中 Hh 受体细胞中蛋白聚糖 Dally 的表达对于高水平但不是低水平的途径活性是必需的，而与它在 Hh 产生细胞中的要求无关。我们证明 Dally 是将 Hh 隔离在细胞表面并促进其与受体内化所必需的。这种内化依赖于水解酶 Notum 和 Dally 的糖基磷脂酰肌醇（GPI）部分的活性，并表明与第二糖蛋白聚糖 Dally-like 在 Hh 信号转导中的作用不同。我们的数据表明，Notum 对 Dally-GPI 的水解通过促进 Hh-Patched 配体受体复合物的内化，提供了从低水平到高水平信号转导的开关。
