Motoyama Jun, Milenkovic Ljiljana, Iwama Mizuho, Shikata Yayoi, Scott Matthew P, Hui Chi-chung
Molecular Neuropathology Group, Brain Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Dev Biol. 2003 Jul 1;259(1):150-61. doi: 10.1016/s0012-1606(03)00159-3.
Sonic hedgehog (Shh) directs the development of ventral cell fates, including floor plate and V3 interneurons, in the mouse neural tube. Here, we show that the transcription factors Gli2 and Gli3, mediators of Shh signaling, are required for the development of the ventral cell fates but make distinct contributions to controlling cell fates at different locations along the rostral-caudal axis. Mutants lacking Patched1 (Ptc1), the putative receptor of Shh, were used to analyze Gli functions. Ptc1(-/-) mutants develop floor plate, motor neuron, and V3 interneuron progenitors in lateral and dorsal regions, suggesting that the normal role of Ptc1 is to suppress ventral cell development in dorsal neural tube. The Ptc1(-/-) phenotype is rescued, with restoration of dorsal cell types, by the lack of Gli2, but only in the caudal neural tube. In triple mutants of Gli2, Gli3, and Ptc1, dorsal and lateral cell fates are restored in the entire neural tube. These observations suggest that Gli2 is essential for ventral specification in the caudal neural tube, and that in more rostral regions, only Gli3 can promote development of ventral cells if Gli2 is absent. Thus, Shh signaling is mediated by overlapping but distinct functions of Gli2 and Gli3, and their relative contributions vary along the rostral-caudal axis.
音猬因子（Shh）指导小鼠神经管中腹侧细胞命运的发育，包括底板和V3中间神经元。在此，我们表明Gli2和Gli3这两种转录因子作为Shh信号的介导因子，对于腹侧细胞命运的发育是必需的，但在沿头-尾轴的不同位置对控制细胞命运有着不同的贡献。利用缺乏Patched1（Ptc1）（Shh的假定受体）的突变体来分析Gli的功能。Ptc1（-/-）突变体在外侧和背侧区域发育出底板、运动神经元和V3中间神经元祖细胞，这表明Ptc1的正常作用是抑制背侧神经管中的腹侧细胞发育。通过缺失Gli2可挽救Ptc1（-/-）的表型，并恢复背侧细胞类型，但仅在尾侧神经管中。在Gli2、Gli3和Ptc1的三重突变体中，整个神经管的背侧和外侧细胞命运得以恢复。这些观察结果表明，Gli2对于尾侧神经管中的腹侧特化至关重要，而在更靠前的区域，如果Gli2缺失，只有Gli3能够促进腹侧细胞的发育。因此，Shh信号是由Gli2和Gli3重叠但不同的功能介导的，并且它们的相对贡献沿头-尾轴有所不同。
