Briscoe J, Sussel L, Serup P, Hartigan-O'Connor D, Jessell T M, Rubenstein J L, Ericson J
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Nature. 1999 Apr 15;398(6728):622-7. doi: 10.1038/19315.
During vertebrate development, the specification of distinct cell types is thought to be controlled by inductive signals acting at different concentration thresholds. The degree of receptor activation in response to these signals is a known determinant of cell fate, but the later steps at which graded signals are converted into all-or-none distinctions in cell identity remain poorly resolved. In the ventral neural tube, motor neuron and interneuron generation depends on the graded activity of the signalling protein Sonic hedgehog (Shh). These neuronal subtypes derive from distinct progenitor cell populations that express the homeodomain proteins Nkx2.2 or Pax6 in response to graded Shh signalling. In mice lacking Pax6, progenitor cells generate neurons characteristic of exposure to greater Shh activity. However, Nkx2.2 expression expands dosally in Pax6 mutants, raising the possibility that Pax6 controls neuronal pattern indirectly. Here we provide evidence that Nkx2.2 has a primary role in ventral neuronal patterning. In Nkx2.2 mutants, Pax6 expression is unchanged but cells undergo a ventral-to-dorsal transformation in fate and generate motor neurons rather than interneurons. Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity.
在脊椎动物发育过程中，不同细胞类型的特化被认为是由作用于不同浓度阈值的诱导信号所控制。已知对这些信号作出反应时受体激活的程度是细胞命运的一个决定因素，但在随后的步骤中，分级信号是如何转化为细胞身份的全或无差异的，仍未得到很好的解决。在腹侧神经管中，运动神经元和中间神经元的产生取决于信号蛋白音猬因子（Shh）的分级活性。这些神经元亚型源自不同的祖细胞群体，它们会根据分级的Shh信号表达同源结构域蛋白Nkx2.2或Pax6。在缺乏Pax6的小鼠中，祖细胞产生的神经元具有接触更高Shh活性时的特征。然而，在Pax6突变体中，Nkx2.2的表达向背侧扩展，这增加了Pax6间接控制神经元模式的可能性。在这里，我们提供证据表明Nkx2.2在腹侧神经元模式形成中起主要作用。在Nkx2.2突变体中，Pax6的表达没有变化，但细胞命运发生了从腹侧到背侧的转变，并产生运动神经元而非中间神经元。因此，Nkx2.2在解读分级的Shh信号和选择神经元身份方面起着至关重要的作用。
