Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling
Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling
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DOI：
10.1242/dev.078402
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发表时间：
2012-09-01
期刊：
影响因子：
4.6
通讯作者：
Gallet, Armel
中科院分区：
文献类型：
--
作者：
Ayers, Katie L.;Mteirek, Rana;Gallet, Armel
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。形态发生素介导的形态发生需要形态发生素水平的精确传感和动态细胞反应，但对此负责的分子机制知之甚少。最近的几项研究表明，参与多蛋白Hh接收复合物，并暗示在Hh传感在细胞表面的一个低估的复杂性。我们在这里表明，蛋白聚糖达利在果蝇的HH-接收细胞的表达是必要的高，但不是低水平的通路活性，独立于其要求在HH-生产细胞。我们证明，达利是必要的螯合Hh在细胞表面，并促进Hh内化与其受体。这种内化依赖于Notum水解酶和Dally的糖基-磷脂酰-肌醇（GPI）部分的活性，并表明偏离了Hh信号传导中第二个磷脂酰肌醇蛋白聚糖Dally样的作用。我们的数据表明，Notum水解Dally-GPI通过促进Hh-补丁配体-受体复合物的内化提供了从低水平到高水平的信号传导。
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.