An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C-elegans
An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C-elegans
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DOI：
10.1242/dev.02494
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发表时间：
2006-09-01
期刊：
影响因子：
4.6
通讯作者：
Hobert, Oliver
中科院分区：
文献类型：
--
作者：
Johnston, Robert J., Jr.;Copeland, John W.;Hobert, Oliver
控制细胞终末分化状态的基因调控网络，总的来说，只是表面上的理解。在一项突变体筛选中，旨在识别基因组的调节因子，这些调节因子定义了两个左/右不对称C的分化状态。elegans味觉神经元，ASEL和ASER，我们已经分离出一个突变体，fozi-1，具有一种新的混合命运表型，其特征在于ASER中ASEL命运的去抑制。fozi-1编码一种蛋白质，其在ASER的细胞核中起作用以抑制LIM同源框基因lim-6、神经肽编码基因和GCY基因家族的推定化学受体的表达。FOZI-1蛋白显示出一种非常不寻常的结构域结构，它结合了两个功能上必需的C2 H2锌指结构域，这可能涉及转录调控，与一个同源性2（FH 2）结构域，通常只在肌动蛋白细胞骨架的胞质调节剂中发现。我们证明FOZI-1的FH 2结构域已经失去了肌动蛋白聚合功能，但保持了其在遗传学上古老的同源二聚体化能力。fozi-1在特定调控网络基序的背景下与几种转录因子和microRNA发生遗传相互作用。这些网络基序赋予系统以特性，这些特性提供了对细胞如何采用其稳定的终末分化状态的见解。
Gene regulatory networks that control the terminally differentiated state of a cell are, by and large, only superficially understood. In a mutant screen aimed at identifying regulators of gene batteries that define the differentiated state of two left/right asymmetric C. elegans gustatory neurons, ASEL and ASER, we have isolated a mutant, fozi-1, with a novel mixed-fate phenotype, characterized by de-repression of ASEL fate in ASER. fozi-1 codes for a protein that functions in the nucleus of ASER to inhibit the expression of the LIM homeobox gene lim-6, neuropeptide-encoding genes and putative chemoreceptors of the GCY gene family. The FOZI-1 protein displays a highly unusual domain architecture, that combines two functionally essential C2H2 zinc-finger domains, which are probably involved in transcriptional regulation, with a formin homology 2 (FH2) domain, normally found only in cytosolic regulators of the actin cytoskeleton. We demonstrate that the FH2 domain of FOZI-1 has lost its actin polymerization function but maintains its phylogenetically ancient ability to homodimerize. fozi-1 genetically interacts with several transcription factors and micro RNAs in the context of specific regulatory network motifs. These network motifs endow the system with properties that provide insights into how cells adopt their stable terminally differentiated states.