Wnt signaling inhibitors regulate the transcriptional response to morphogenetic Shh-Gli signaling in the neural tube
Wnt signaling inhibitors regulate the transcriptional response to morphogenetic Shh-Gli signaling in the neural tube
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DOI：
10.1016/j.devcel.2006.06.013
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发表时间：
2006-09-01
影响因子：
11.8
通讯作者：
Matise, Michael P.
中科院分区：
文献类型：
--
作者：
Lei, Qiubo;Jeong, Yongsu;Matise, Michael P.
Shh-Gli信号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，限制靶基因对特定结构域的反应的分子机制尚不清楚。在这里，我们表明，Wnt通路抑制剂调节腹侧Shh靶基因Nkx2.2的阈值反应，以建立其在腹侧脊髓中的限制性表达。Nkx2.2增强子的鉴定和表征揭示了表达直接受正Shh-Gli信号传导和负Tcf阻遏物活性调节。我们的数据表明，Nkx2.2的背侧限制控制Tcf 4介导的转录抑制，而不是由高水平的Shh-Gli信号的直接要求，反对一个简单的模型的基础上差异Gli因子在靶基因的亲和力。这些结果确定了一个转录机制，整合分级Shh和Wnt信号传导，以确定祖基因的表达结构域和神经管中的细胞命运。
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.