Liem K F, Jessell T M, Briscoe J
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.
Development. 2000 Nov;127(22):4855-66. doi: 10.1242/dev.127.22.4855.
The secretion of Sonic hedgehog (Shh) from the notochord and floor plate appears to generate a ventral-to-dorsal gradient of Shh activity that directs progenitor cell identity and neuronal fate in the ventral neural tube. In principle, the establishment of this Shh activity gradient could be achieved through the graded distribution of the Shh protein itself, or could depend on additional cell surface or secreted proteins that modify the response of neural cells to Shh. Cells of the neural plate differentiate from a region of the ectoderm that has recently expressed high levels of BMPs, raising the possibility that prospective ventral neural cells are exposed to residual levels of BMP activity. We have examined whether modulation of the level of BMP signaling regulates neural cell responses to Shh, and thus might contribute to the patterning of cell types in the ventral neural tube. Using an in vitro assay of neural cell differentiation we show that BMP signaling markedly alters neural cell responses to Shh signals, eliciting a ventral-to-dorsal switch in progenitor cell identity and neuronal fate. BMP signaling is regulated by secreted inhibitory factors, including noggin and follistatin, both of which are expressed in or adjacent to the neural plate. Conversely, follistatin but not noggin produces a dorsal-to-ventral switch in progenitor cell identity and neuronal fate in response to Shh both in vitro and in vivo. These results suggest that the specification of ventral neural cell types depends on the integration of Shh and BMP signaling activities. The net level of BMP signaling within neural tissue may be regulated by follistatin and perhaps other BMP inhibitors secreted by mesodermal cell types that flank the ventral neural tube.
脊索和底板分泌的音猬因子（Shh）似乎会产生一种从腹侧到背侧的Shh活性梯度，该梯度引导腹侧神经管中祖细胞的特性和神经元命运。原则上，这种Shh活性梯度的建立可以通过Shh蛋白本身的梯度分布来实现，或者可能取决于其他细胞表面蛋白或分泌蛋白，这些蛋白会改变神经细胞对Shh的反应。神经板细胞由最近表达高水平骨形态发生蛋白（BMP）的外胚层区域分化而来，这增加了未来腹侧神经细胞暴露于残余水平BMP活性的可能性。我们研究了BMP信号水平的调节是否会调节神经细胞对Shh的反应，从而可能有助于腹侧神经管中细胞类型的模式形成。通过神经细胞分化的体外实验，我们发现BMP信号显著改变了神经细胞对Shh信号的反应，引发了祖细胞特性和神经元命运从腹侧到背侧的转变。BMP信号受分泌的抑制因子调节，包括头蛋白和卵泡抑素，它们都在神经板内或其附近表达。相反，卵泡抑素而非头蛋白在体外和体内都会使祖细胞特性和神经元命运在对Shh的反应中发生从背侧到腹侧的转变。这些结果表明，腹侧神经细胞类型的特化取决于Shh和BMP信号活性的整合。神经组织内BMP信号的净水平可能受卵泡抑素以及也许由腹侧神经管两侧的中胚层细胞类型分泌的其他BMP抑制剂调节。
