Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, California, USA.
Dev Dyn. 2012 Feb;241(2):247-56. doi: 10.1002/dvdy.23726.
The Frontonasal Ectodermal Zone (FEZ) is a signaling center in the face that expresses Sonic hedgehog (Shh) and regulates patterned growth of the upper jaw. Blocking SHH in the forebrain blocks Shh expression in the FEZ and creates malformations resembling holoprosencephaly (HPE), while inhibition of BMP signaling in the mesenchyme blocks FEZ formation and causes similar dysmorphology. Thus, the brain could regulate FEZ formation by SHH or BMP signaling, and if so, activating one of these pathways in the face might alleviate the effects of repression of SHH in the brain.
We blocked SHH signaling in the brain while adding SHH or BMP between the neural and facial ectoderm of the frontonasal process. When applied early, SHH restored Shh expression in the FEZ and significantly improved shape outcomes, which contrasts with our previous experiments that showed later SHH treatments have no effect. BMP-soaked beads introduced early and late caused apoptosis that exacerbated malformations. Finally, removal of Smoothened from neural crest cells did not inhibit Shh expression in the FEZ.
Collectively, this work suggests that a direct, time-sensitive SHH signal from the brain is required for the later induction of Shh in the FEZ. We propose a testable model of FEZ activation and discuss signaling mediators that may regulate these interactions.
额鼻外胚层区（FEZ）是面部的一个信号中心，表达 Sonic hedgehog（Shh）并调节上颌的图案生长。在前脑中阻断 SHH 会阻止 FEZ 中的 Shh 表达，并产生类似于全前脑畸形（HPE）的畸形，而在间质中抑制 BMP 信号会阻止 FEZ 形成并导致类似的畸形。因此，大脑可以通过 SHH 或 BMP 信号来调节 FEZ 的形成，如果是这样，在前部激活这些途径中的一种可能会减轻大脑中 SHH 抑制的影响。
我们在脑内阻断 SHH 信号，同时在前额鼻突的神经外胚层和面部外胚层之间添加 SHH 或 BMP。早期应用时，SHH 恢复了 FEZ 中的 Shh 表达，并显著改善了形状结果，这与我们之前的实验结果形成对比，表明晚期 SHH 处理没有效果。早期和晚期引入的 BMP 浸泡珠引起了凋亡，加剧了畸形。最后，从神经嵴细胞中去除 Smoothened 并没有抑制 FEZ 中的 Shh 表达。
总的来说，这项工作表明，大脑中需要一个直接的、时间敏感的 SHH 信号来在 FEZ 中诱导 Shh 的后期表达。我们提出了一个可测试的 FEZ 激活模型，并讨论了可能调节这些相互作用的信号介质。
