Toker Anne S, Teng Yingqi, Ferreira Henrique B, Emmons Scott W, Chalfie Martin
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Development. 2003 Aug;130(16):3831-40. doi: 10.1242/dev.00398.
Members of the spalt (sal) gene family encode zinc-finger proteins that are putative tumor suppressors and regulate anteroposterior (AP) patterning, cellular identity, and, possibly, cell cycle progression. The mechanism through which sal genes carry out these functions is unclear. The Caenorhabditis elegans sal gene sem-4 controls the fate of several different cell types, including neurons, muscle and hypodermis. Mutation of sem-4 transforms particular tail neurons into touch-neuron-like cells. In wild-type C. elegans, six touch receptor neurons mediate the response of the worm to gentle touch. All six touch neurons normally express the LIM homeobox gene mec-3. A subset, the two PLM cells, also express the Hox gene egl-5, an Abdominal-B homolog, which we find is required for correct mec-3 expression in these cells. The abnormal touch-neuron-like-cells in sem-4 animals express mec-3; we show that a subset also express egl-5. We report: (1) that ectopic expression of sem-4 in normal touch cells represses mec-3 expression and reduces touch cell function; (2) that egl-5 expression is required for both the fate of normal PLM touch neurons in wild-type animals and the fate of a subset of abnormal touch neurons in sem-4 animals, and (3) that SEM-4 specifically binds a shared motif in the mec-3 and egl-5 promoters that mediates repression of these genes in cells in the tail. We conclude that sem-4 represses egl-5 and mec-3 through direct interaction with regulatory sequences in the promoters of these genes, that sem-4 indirectly modulates mec-3 expression through its repression of egl-5 and that this negative regulation is required for proper determination of neuronal fates. We suggest that the mechanism and targets of regulation by sem-4 are conserved throughout the sal gene family: other sal genes might regulate patterning and cellular identity through direct repression of Hox selector genes and effector genes.
spalt（sal）基因家族的成员编码锌指蛋白，这些蛋白被认为是肿瘤抑制因子，可调节前后轴（AP）模式形成、细胞特性，还可能调节细胞周期进程。sal基因执行这些功能的机制尚不清楚。秀丽隐杆线虫的sal基因sem-4控制着几种不同细胞类型的命运，包括神经元、肌肉和皮下组织。sem-4的突变会将特定的尾部神经元转化为类似触觉神经元的细胞。在野生型秀丽隐杆线虫中，六个触觉受体神经元介导线虫对轻柔触摸的反应。所有六个触觉神经元通常都表达LIM同源框基因mec-3。其中一部分，即两个PLM细胞，还表达Hox基因egl-5，它是Abdominal-B的同源物，我们发现它是这些细胞中mec-3正确表达所必需的。sem-4突变动物中异常的类似触觉神经元的细胞表达mec-3；我们发现其中一部分也表达egl-5。我们报告：（1）正常触觉细胞中sem-4的异位表达会抑制mec-3的表达并降低触觉细胞的功能；（2）egl-5的表达对于野生型动物中正常PLM触觉神经元的命运以及sem-4突变动物中一部分异常触觉神经元的命运都是必需的；（3）SEM-4特异性结合mec-3和egl-5启动子中的一个共同基序，该基序介导这些基因在尾部细胞中的抑制作用。我们得出结论，sem-4通过与这些基因启动子中的调控序列直接相互作用来抑制egl-5和mec-3，sem-4通过抑制egl-5间接调节mec-3的表达，并且这种负调控对于正确确定神经元命运是必需的。我们认为sem-4的调控机制和靶点在整个sal基因家族中是保守的：其他sal基因可能通过直接抑制Hox选择基因和效应基因来调节模式形成和细胞特性。
