Ybot-Gonzalez Patricia, Gaston-Massuet Carles, Girdler Gemma, Klingensmith John, Arkell Ruth, Greene Nicholas D E, Copp Andrew J
Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Development. 2007 Sep;134(17):3203-11. doi: 10.1242/dev.008177.
Dorsolateral bending of the neural plate, an undifferentiated pseudostratified epithelium, is essential for neural tube closure in the mouse spinal region. If dorsolateral bending fails, spina bifida results. In the present study, we investigated the molecular signals that regulate the formation of dorsolateral hinge points (DLHPs). We show that Bmp2 expression correlates with upper spinal neurulation (in which DLHPs are absent); that Bmp2-null embryos exhibit premature, exaggerated DLHPs; and that the local release of Bmp2 inhibits neural fold bending. Therefore, Bmp signalling is necessary and sufficient to inhibit DLHPs. By contrast, the Bmp antagonist noggin is expressed dorsally in neural folds containing DLHPs, noggin-null embryos show markedly reduced dorsolateral bending and local release of noggin stimulates bending. Hence, Bmp antagonism is both necessary and sufficient to induce dorsolateral bending. The local release of Shh suppresses dorsal noggin expression, explaining the absence of DLHPs at high spinal levels, where notochordal expression of Shh is strong. DLHPs ;break through' at low spinal levels, where Shh expression is weaker. Zic2 mutant embryos fail to express Bmp antagonists dorsally and lack DLHPs, developing severe spina bifida. Our findings reveal a molecular mechanism based on antagonism of Bmp signalling that underlies the regulation of DLHP formation during mouse spinal neural tube closure.
神经板是一种未分化的假复层上皮，其背外侧弯曲对于小鼠脊髓区域的神经管闭合至关重要。如果背外侧弯曲失败，就会导致脊柱裂。在本研究中，我们调查了调节背外侧铰链点（DLHP）形成的分子信号。我们发现，Bmp2的表达与上脊髓神经形成相关（其中不存在DLHP）；Bmp2基因敲除胚胎表现出过早、过度的DLHP；并且局部释放Bmp2会抑制神经褶弯曲。因此，Bmp信号传导对于抑制DLHP是必要且充分的。相比之下，Bmp拮抗剂头蛋白在含有DLHP的神经褶中背侧表达，头蛋白基因敲除胚胎的背外侧弯曲明显减少，局部释放头蛋白会刺激弯曲。因此，Bmp拮抗作用对于诱导背外侧弯曲既是必要的也是充分的。Shh的局部释放会抑制背侧头蛋白的表达，这解释了在脊髓较高水平（此处Shh的脊索表达较强）不存在DLHP的原因。在脊髓较低水平（此处Shh表达较弱），DLHP“突破”。Zic2突变胚胎无法在背侧表达Bmp拮抗剂且缺乏DLHP，从而发展为严重的脊柱裂。我们的研究结果揭示了一种基于Bmp信号拮抗作用的分子机制，该机制是小鼠脊髓神经管闭合过程中DLHP形成调控的基础。
