LRP2 Is an Auxiliary SHH Receptor Required to Condition the Forebrain Ventral Midline for Inductive Signals
LRP2 Is an Auxiliary SHH Receptor Required to Condition the Forebrain Ventral Midline for Inductive Signals
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DOI：
10.1016/j.devcel.2011.11.023
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发表时间：
2012-02-14
影响因子：
11.8
通讯作者：
Hammes, Annette
中科院分区：
文献类型：
--
作者：
Christ, Annabel;Christa, Anna;Hammes, Annette
Sonic hedgehog(SHH)是一种前脑发育的调节剂，通过其受体Patched 1发挥作用。然而，对神经形成的细胞机制知之甚少，在神经形成过程中，来自前索板的SHH控制着主要的前脑组织者--吻侧间脑腹中线(RDVM)的规范。我们发现LRP2是低密度脂蛋白受体基因家族的成员，是RDVM中SHH信号机制的一个组成部分。LRP2作为顶端SHH结合蛋白，将SHH隔离在靶区，控制SHH/Patched1复合体的内化和细胞转运。在小鼠和头部外植体中缺乏LRP2导致对SHH的反应失败，尽管Patched 1和Smooth功能表达，而LRP2变体在细胞中的过表达增加了SHH的信号转导能力。我们的数据确定了LRP2在SHH信号中的关键作用，并揭示了Lrp2缺陷小鼠和患者前脑异常的分子机制。
Sonic hedgehog (SHH) is a regulator of forebrain development that acts through its receptor, patched 1. However, little is known about cellular mechanisms at neurulation, whereby SHH from the prechordal plate governs specification of the rostral diencephalon ventral midline (RDVM), a major forebrain organizer. We identified LRP2, a member of the LDL receptor gene family, as a component of the SHH signaling machinery in the RDVM. LRP2 acts as an apical SHH-binding protein that sequesters SHH in its target field and controls internalization and cellular trafficking of SHH/patched 1 complexes. Lack of LRP2 in mice and in cephalic explants results in failure to respond to SHH, despite functional expression of patched 1 and smoothened, whereas overexpression of LRP2 variants in cells increases SHH signaling capacity. Our data identify a critical role for LRP2 in SHH signaling and reveal the molecular mechanism underlying forebrain anomalies in mice and patients with Lrp2 defects.