Spoelgen Robert, Hammes Annette, Anzenberger Uwe, Zechner Dietmar, Andersen Olav M, Jerchow Boris, Willnow Thomas E
Max-Delbrueck-Center for Molecular Medicine, Berlin, 13092, Germany.
Development. 2005 Jan;132(2):405-14. doi: 10.1242/dev.01580.
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.
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。基因敲除小鼠中巨蛋白表达缺失会导致前脑无裂畸形，这表明其在前脑发育中具有一种重要但尚未明确的功能。我们利用在胚胎中完全或条件性失活巨蛋白基因的小鼠来证明，神经上皮而非卵黄囊中巨蛋白的表达对脑发育至关重要。在前脑早期发育过程中，巨蛋白缺乏会导致骨形态发生蛋白（Bmp）4在 Rostral 背侧神经上皮中的表达和信号传导增加，随后腹侧前脑的音猬因子（Shh）表达丧失。由于缺乏 SHH 活性，腹侧来源的少突胶质细胞和中间神经元细胞群在巨蛋白基因敲除胚胎的前脑中丢失。在通过 BMPs（神经管模式形成的中央调节因子）增强信号传导的模型中也观察到类似缺陷。由于巨蛋白介导 BMP4 的内吞摄取和降解，这些发现表明巨蛋白在神经管特化中发挥作用，可能是通过作为神经上皮中的 BMP4 清除受体来实现的。
