The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms.
The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms.
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DOI：
10.1016/j.ydbio.2006.03.051
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发表时间：
2006-07
影响因子：
2.7
通讯作者：
R. Stottmann;Mark Berrong;Karen M. Matta;Murim Choi;J. Klingensmith
中科院分区：
文献类型：
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作者：
R. Stottmann;Mark Berrong;Karen M. Matta;Murim Choi;J. Klingensmith
在这里，我们通过分析缺乏 BMP 拮抗剂 Noggin 的小鼠，描述了骨形态发生蛋白 (BMP) 信号传导升高对神经管形态发生的影响。 Noggin 在闭合神经皱襞的背侧表达，在脊索和体节的腹侧表达。所有Noggin-/-幼崽出生时都患有腰椎裂；根据遗传背景，他们也可能患有外脑畸形。外脑畸形是由于中脑/后脑背外侧铰链点 (DLHP) 形成缺乏而导致的原发性神经系统故障所致。因此，如先前在脊髓水平的 Shh 信号传导所示，BMP 活性可能会抑制颅骨 DLHP 形态发生。然而，在Noggin−/−背侧神经管中观察到的BMP信号增加不足以引起脑外畸形；它似乎还取决于基因修饰剂的作用，该基因修饰剂可能会增强背部的“嘘”信号。脊髓神经管缺陷是由不同的机制引起的：肢芽之间的中胚层中 BMP 信号传导增加导致体节分化异常和轴性骨骼畸形。由此导致神经管缺乏机械支撑，导致脊柱裂。我们发现这种缺陷是由于 BMP4 信号传导升高所致。因此，在两种情况下，Noggin 是哺乳动物神经形成所必需的，具体取决于沿头尾轴的位置。
Here we characterize the consequences of elevated bone morphogenetic protein (BMP) signaling on neural tube morphogenesis by analyzing mice lacking the BMP antagonist, Noggin. Noggin is expressed dorsally in the closing neural folds and ventrally in the notochord and somites. All Noggin−/−pups are born with lumbar spina bifida; depending on genetic background, they may also have exencephaly. The exencephaly is due to a primary failure of neurulation, resulting from a lack of mid/hindbrain dorsolateral hinge point (DLHP) formation. Thus, as previously shown for Shh signaling at spinal levels, BMP activity may inhibit cranial DLHP morphogenesis. However, the increased BMP signaling observed in the Noggin−/−dorsal neural tube is not sufficient to cause exencephaly; it appears to also depend on the action of a genetic modifier, which may act to increase dorsal Shh signaling. The spinal neural tube defect results from a different mechanism: increased BMP signaling in the mesoderm between the limb buds leads to abnormal somite differentiation and axial skeletal malformation. The resulting lack of mechanical support for the neural tube causes spina bifida. We show that this defect is due to elevated BMP4 signaling. Thus, Noggin is required for mammalian neurulation in two contexts, dependent on position along the rostrocaudal axis.