Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation.
Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation.
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DOI：
10.1523/jneurosci.0901-11.2011
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发表时间：
2011-07-06
期刊：
影响因子：
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通讯作者：
Turner EE
中科院分区：
文献类型：
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作者：
Dykes IM;Tempest L;Lee SI;Turner EE
转录因子的组合表达经常标记神经系统中的细胞身份，但这些因子如何相互作用以确定特定的神经元表型还没有很好地理解。三叉神经（TG）和背根神经节（DRG）的感觉神经元共表达同源结构域转录因子Brn 3a和Islet 1，过去的工作已经揭示了这些因子下游基因表达的部分重叠程序。在这里，我们研究Brn 3a/Islet 1双敲除小鼠（DKO小鼠）的感觉发育。感觉神经发生以及TG和DRG的形成发生在DKO胚胎中，但DRG背侧移位，并且神经节的外周投射明显受到干扰。DKO胚胎中的感觉神经元显示出感觉亚型的所有早期标志物的严重损失，包括Ntrk神经营养因子受体和Runx 1和Runx 3家族转录因子。在E12.5 DRG的单突变和双突变胚胎的全球基因表达的检查表明，Brn 3a和Islet 1是共同需要的几乎所有方面的感官特异性基因表达，包括几个新发现的感官标记。在大多数靶标上，Brn 3a和Islet 1表现出负上位性，其中单个敲除等位基因的效应小于DKO中的加性效应。较小的靶点子集表现出正上位性，或仅由一个因子调节。Brn 3a/Islet 1双突变体也不能在发育上抑制神经源性bHLH基因，体内染色质免疫沉淀显示Islet 1与neurod 4基因中已知的Brn 3a调节增强子结合，表明这些基因之间存在相互作用机制。
The combinatorial expression of transcription factors frequently marks cellular identity in the nervous system, yet how these factors interact to determine specific neuronal phenotypes is not well understood. Sensory neurons of the trigeminal (TG) and dorsal root ganglia (DRG) co-express the homeodomain transcription factors Brn3a and Islet1, and past work has revealed partially overlapping programs of gene expression downstream of these factors. Here we examine sensory development in Brn3a/Islet1 double knockout mice (DKO mice). Sensory neurogenesis and the formation of the TG and DRG occur in DKO embryos, but the DRG are dorsally displaced, and the peripheral projections of the ganglia are markedly disturbed. Sensory neurons in DKO embryos show a profound loss of all early markers of sensory subtypes, including the Ntrk neurotrophin receptors, and the runt-family transcription factors Runx1 and Runx3. Examination of global gene expression in the E12.5 DRG of single and double mutant embryos shows that Brn3a and Islet1 are together required for nearly all aspects of sensory-specific gene expression, including several newly identified sensory markers. On a majority of targets Brn3a and Islet1 exhibit negative epistasis, in which the effects of the individual knockout alleles are less than additive in the DKO. Smaller subsets of targets exhibit positive epistasis, or are regulated exclusively by one factor. Brn3a/Islet1 double mutants also fail to developmentally repress neurogenic bHLH genes, and in vivo chromatin immunoprecipitation shows that Islet1 binds to a known Brn3a -regulated enhancer in the neurod4 gene, suggesting a mechanism of interaction between these genes.