Max-Delbrück-Center for Molecular Medicine, Charité Universitätsmedizin, D-13125 Berlin, Germany.
Dev Cell. 2012 Feb 14;22(2):268-78. doi: 10.1016/j.devcel.2011.11.023.
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.
声波刺猬蛋白（SHH）是调节前脑发育的一种蛋白，它通过其受体 patched 1 发挥作用。然而，在神经管形成过程中，SHH 来自脑前板，调节头部端脑腹中线（RDVM）的指定，而 RDVM 是大脑主要组织者，对于细胞机制却知之甚少。我们鉴定出 LRP2 是 LDL 受体基因家族的一个成员，是 RDVM 中 SHH 信号机制的一个组成部分。LRP2 作为一个顶端 SHH 结合蛋白，将 SHH 隔离在其靶场，并控制 SHH/patched 1 复合物的内化和细胞运输。尽管 patched 1 和 smoothened 的功能表达，但在小鼠和头部分离物中缺乏 LRP2 会导致对 SHH 无反应，而细胞中 LRP2 变体的过表达会增加 SHH 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，并揭示了小鼠和 Lrp2 缺陷患者前脑异常的分子机制。
