Gata3 participates in a complex transcriptional feedback network to regulate sympathoadrenal differentiation
Gata3 participates in a complex transcriptional feedback network to regulate sympathoadrenal differentiation
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DOI：
10.1242/dev.02553
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发表时间：
2006-10-01
期刊：
影响因子：
4.6
通讯作者：
Engel, James Douglas
中科院分区：
文献类型：
--
作者：
Moriguchi, Takashi;Takako, Nakano;Engel, James Douglas
Gata 3突变小鼠在胚胎第（E）11天因去甲肾上腺素能缺陷而死亡，并且可以通过使用人DBH启动子指导Gata 3转基因表达来恢复Gata 3功能而被拯救，或者如这里所示，特异性地在交感肾上腺（SA）谱系中恢复Gata 3功能。在Gata 3基因缺失的胚胎中，SA分化明显受损，肾上腺嗜铬细胞和交感神经元凋亡增加。此外，对Gata 3突变体纯化的嗜铬细胞的mRNA分析表明，Mash 1、Hand 2和Phox 2b（假定的Gata 3上游调节因子）以及终末分化的SA谱系产物（酪氨酸羟化酶（Th）和多巴胺β-羟化酶（Dbh））的水平显着改变。然而，在Gata 3突变体背景中Gata 3功能的SA谱系特异性恢复拯救了下游以及推定的上游基因的表达表型。这些数据不仅强调了Gata 3对SA细胞的分化和存活至关重要的假设，而且还表明它们的分化是由SA谱系中Gata 3，Mash 1，Hand 2和Phox 2b之间相互加强的反馈转录相互作用控制的。
Gata3 mutant mice expire of noradrenergic deficiency by embryonic day ( E) 11 and can be rescued pharmacologically or, as shown here, by restoring Gata3 function specifically in sympathoadrenal ( SA) lineages using the human DBH promoter to direct Gata3 transgenic expression. In Gata3-null embryos, there was significant impairment of SA differentiation and increased apoptosis in adrenal chromaffin cells and sympathetic neurons. Additionally, mRNA analyses of purified chromaffin cells from Gata3 mutants show that levels of Mash1, Hand2 and Phox2b ( postulated upstream regulators of Gata3) as well as terminally differentiated SA lineage products ( tyrosine hydroxylase, Th, and dopamine beta-hydroxylase, Dbh) are markedly altered. However, SA lineage-specific restoration of Gata3 function in the Gata3 mutant background rescues the expression phenotypes of the downstream, as well as the putative upstream genes. These data not only underscore the hypothesis that Gata3 is essential for the differentiation and survival of SA cells, but also suggest that their differentiation is controlled by mutually reinforcing feedback transcriptional interactions between Gata3, Mash1, Hand2 and Phox2b in the SA lineage.