Lei Qiubo, Jeong Yongsu, Misra Kamana, Li Shike, Zelman Alice K, Epstein Douglas J, Matise Michael P
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, 08854, USA.
Dev Cell. 2006 Sep;11(3):325-37. doi: 10.1016/j.devcel.2006.06.013.
Shh-Gli signaling controls cell fates in the developing ventral neural tube by regulating the patterned expression of transcription factors in neural progenitors. However, the molecular mechanisms that limit target gene responses to specific domains are unclear. Here, we show that Wnt pathway inhibitors regulate the threshold response of a ventral Shh target gene, Nkx2.2, to establish its restricted expression in the ventral spinal cord. Identification and characterization of an Nkx2.2 enhancer reveals that expression is directly regulated by positive Shh-Gli signaling and negative Tcf repressor activity. Our data indicate that the dorsal limit of Nkx2.2 is controlled by Tcf4-mediated transcriptional repression, and not by a direct requirement for high-level Shh-Gli signaling, arguing against a simple model based on differential Gli factor affinities in target genes. These results identify a transcriptional mechanism that integrates graded Shh and Wnt signaling to define progenitor gene expression domains and cell fates in the neural tube.
Shh-Gli信号通路通过调节神经祖细胞中转录因子的模式化表达来控制发育中的腹侧神经管中的细胞命运。然而，限制靶基因对特定区域作出反应的分子机制尚不清楚。在这里，我们表明Wnt信号通路抑制剂调节腹侧Shh靶基因Nkx2.2的阈值反应，以在腹侧脊髓中建立其限制性表达。对Nkx2.2增强子的鉴定和表征表明，其表达直接受正向Shh-Gli信号通路和负向Tcf阻遏物活性的调控。我们的数据表明，Nkx2.2的背侧界限是由Tcf4介导的转录抑制所控制，而不是由对高水平Shh-Gli信号通路的直接需求所控制，这与基于靶基因中Gli因子亲和力差异的简单模型相悖。这些结果确定了一种转录机制，该机制整合了分级的Shh和Wnt信号，以定义神经管中的祖细胞基因表达域和细胞命运。
