A Pbx1-dependent genetic and transcriptional network regulates spleen ontogeny
A Pbx1-dependent genetic and transcriptional network regulates spleen ontogeny
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DOI：
10.1242/dev.01884
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发表时间：
2005-07-01
期刊：
影响因子：
4.6
通讯作者：
Selleri, L
中科院分区：
文献类型：
--
作者：
Brendolan, A;Ferretti, E;Selleri, L
脾是一个重要的淋巴器官，对细胞命运的指定、形态发生和扩张的遗传控制还知之甚少。最近对突变小鼠的研究涉及多种转录因子与脾发育有关，但这些因子之间的等级关系尚未被探索。在这篇报道中，我们通过分析脾小鼠转录因子Pbx1、Hox11(Tlx1)、Nkx3.2(Bapx1)和Pod1(胶囊蛋白，TCF21)的突变，建立了一个调节脾个体发育的遗传网络。我们发现，在Pbx1纯合子突变((-/-))胚胎的脾原基中，Hox11和NKX2.5是最早的已知的脾祖细胞标记之一，这意味着在脾细胞规格中故事中的同源蛋白Pbx1。Pbx1和Hox11在脾的形成中存在遗传上的相互作用，其中任何一种的缺失都与祖细胞增殖减少和脾原基扩张失败有关。染色质免疫沉淀分析表明，Pbx1与脾间充质细胞中的Hox11启动子结合，共同表达Pbx1和Hox11。此外，Hox11在体内与自己的启动子结合，并与TALE蛋白协同作用激活转录，支持其在自动调节电路中的作用。这些研究在脾个体发育中建立了依赖于Pbx1-Hox11的遗传和转录途径。此外，我们还证明了Nkx3.2和Pod1通过不同的途径控制脾的发育，而Pbx1在基因上调节这两条途径中的关键角色，从而成为脾发生中的一个中央等级辅助调节因子。
The genetic control of cell fate specification, morphogenesis and expansion of the spleen, a crucial lymphoid organ, is poorly understood. Recent studies of mutant mice implicate various transcription factors in spleen development, but the hierarchical relationships between these factors have not been explored. In this report, we establish a genetic network that regulates spleen ontogeny, by analyzing asplenic mice mutant for the transcription factors Pbx1, Hox11 (Tlx1), Nkx3.2 (Bapx1) and Pod1 (capsulin, Tcf21). We show that Hox11 and Nkx2.5, among the earliest known markers for splenic progenitor cells, are absent in the splenic anlage of Pbx1 homozygous mutant ((-/-)) embryos, implicating the TALE homeoprotein Pbx1 in splenic cell specification. Pbx1 and Hox11 genetically interact in spleen formation and loss of either is associated with a similar reduction of progenitor cell proliferation and failed expansion of the splenic anlage. Chromatin immunoprecipitation assays show that Pbx1 binds to the Hox11 promoter in spleen mesenchymal cells, which co-express Pbx1 and Hox11. Furthermore, Hox11 binds its own promoter in vivo and acts synergistically with TALE proteins to activate transcription, supporting its role in an auto-regulatory circuit. These studies establish a Pbx1-Hox11-dependent genetic and transcriptional pathway in spleen ontogeny. Additionally, we demonstrate that while Nkx3.2 and Pod1 control spleen development via separate pathways, Pbx1 genetically regulates key players in both pathways, and thus emerges as a central hierarchical coregulator in spleen genesis.