Inhibition of Sonic hedgehog signaling in vivo results in craniofacial neural crest cell death
Inhibition of Sonic hedgehog signaling in vivo results in craniofacial neural crest cell death
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DOI：
10.1016/s0960-9822(00)80052-4
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发表时间：
1999-11-18
期刊：
影响因子：
9.2
通讯作者：
Bronner-Fraser, M
中科院分区：
文献类型：
--
作者：
Ahlgren, SC;Bronner-Fraser, M
背景：声波刺猬 (Shh) 以其在组织图案化（包括头部结构）中的作用而闻名。人类 SHH 的单倍体不足会导致前脑无裂畸形，这是一种以面部和前脑异常为特征的综合征。 Shh null 小鼠具有独眼和鳃弓结构丧失。然而，目前尚不清楚这些表型是否仅源于Shh在中线结构模式化中的早期功能，或者Shh是否在头部发育中发挥其他作用。结果：为了解决底板诱导后Shh的作用，我们通过将分泌功能阻断性抗Shh抗体的杂交瘤细胞注射到鸡颅间充质中来抑制Shh信号传导。该抗体随后与底板、脊索和咽内胚层中的 Shh 结合。这一阶段的Shh信号扰动导致1天后头部尺寸显着减小，2天后鳃弓结构丧失，7天后胚胎头部变小。 1天后神经管和神经嵴细胞死亡显着增加，且神经嵴细胞死亡并非继发于神经管细胞损失。结论：神经管闭合后Shh信号传导减少导致神经管细胞增殖短暂减少，神经管和神经嵴细胞死亡广泛增加，进而导致头部尺寸减小。 Shh 减少后观察到的表型与颅神经嵴消融后观察到的表型相似。因此，我们的结果证明了Shh在协调神经管和颅神经嵴细胞的增殖和存活中的作用。
Background: Sonic hedgehog (Shh) is well known for its role in patterning tissues, including structures of the head. Haploinsufficiency for SHH in humans results in holoprosencephaly, a syndrome characterized by facial and forebrain abnormalities. Shh null mice have cyclopia and loss of branchial arch structures. It is unclear, however, whether these phenotypes arise solely from the early function of Shh in patterning midline structures, or whether Shh plays other roles in head development.Results: To address the role of Shh after floorplate induction, we inhibited Shh signaling by injecting hybridoma cells that secrete a function-blocking anti-Shh antibody into the chick cranial mesenchyme. The antibody subsequently bound to Shh in the floorplate, notochord, and the pharyngeal endoderm. Perturbation of Shh signaling at this stage resulted in a significant reduction in head size after 1 day, loss of branchial arch structures after 2 days, and embryos with smaller heads after 7 days. Cell death was significantly increased in the neural tube and neural crest after 1 day, and neural crest cell death was not secondary to the loss of neural tube cells.Conclusions: Reduction of Shh signaling after neural tube closure resulted in a transient decrease in neural tube cell proliferation and an extensive increase in cell death in the neural tube and neural crest, which in turn resulted in decreased head size. The phenotypes observed after reduction of Shh are similar to those observed after cranial neural crest ablation. Thus, our results demonstrate a role for Shh in coordinating the proliferation and survival of cells of the neural tube and cranial neural crest.