LRP2/megalin is required for patterning of the ventral telencephalon
LRP2/megalin is required for patterning of the ventral telencephalon
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DOI：
10.1242/dev.01580
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发表时间：
2005-01-01
期刊：
影响因子：
4.6
通讯作者：
Willnow, TE
中科院分区：
文献类型：
--
作者：
Spoelgen, R;Hammes, A;Willnow, TE
巨蛋白是一种低密度脂蛋白受体相关蛋白(LRP2)，在早期胚胎的神经上皮和卵黄囊中表达。在基因敲除的小鼠中，缺乏megalin的表达会导致全前脑发育，这表明在前脑发育中有一种重要的但尚未确定的功能。我们使用胚胎中巨蛋白基因完全或有条件失活的小鼠来证明，巨蛋白在神经上皮中的表达，而不是在卵黄囊中的表达，对大脑发育至关重要。在前脑发育早期，巨蛋白缺乏导致骨形态发生蛋白4(BMP)4在头端背侧神经上皮细胞中的表达和信号增加，随后在腹侧前脑中Sonic Hedgehog(Shh)的表达丢失。由于缺乏SHH活性，在megalin(-/-)胚胎的前脑中，腹侧来源的少突胶质细胞和神经元间细胞群丢失。类似的缺陷在通过骨形成蛋白增强信号的模型中也可以看到，骨形成蛋白是神经管模式的中央调节因子。由于megalin介导BMP4的内吞和降解，这些发现表明megalin在神经管规范中的作用，可能是通过在神经上皮细胞中作为BMP4清除受体来发挥作用。
Megalin is a low-density lipoprotein receptor-related protein (LRP2) expressed in the neuroepithelium and the yolk sac of the early embryo. Absence of megalin expression in knockout mice results in holoprosencephaly, indicating an essential yet unidentified function in forebrain development. We used mice with complete or conditional megalin gene inactivation in the embryo to demonstrate that expression of megalin in the neuroepithelium but not in the yolk sac is crucial for brain development. During early forebrain development, megalin deficiency leads to an increase in bone morphogenic protein (Bmp) 4 expression and signaling in the rostral dorsal neuroepithelium, and a subsequent loss of sonic hedgehog (Shh) expression in the ventral forebrain. As a consequence of absent SHH activity, ventrally derived oligodendroglial and interneuronal cell populations are lost in the forebrain of megalin(-/-) embryos. Similar defects are seen in models with enhanced signaling through BMPs, central regulators of neural tube patterning. Because megalin mediates endocytic uptake and degradation of BMP4, these findings indicate a role for megalin in neural tube specification, possibly by acting as BMP4 clearance receptor in the neuroepithelium.