Patterson G I, Koweek A, Wong A, Liu Y, Ruvkun G
Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114 USA.
Genes Dev. 1997 Oct 15;11(20):2679-90. doi: 10.1101/gad.11.20.2679.
Signals from TGF-beta superfamily receptors are transduced to the nucleus by Smad proteins, which transcriptionally activate target genes. In Caenorhabditis elegans, defects in a TGF-beta-related pathway cause a reversible developmental arrest and metabolic shift at the dauer larval stage. Null mutations in daf-3 suppress mutations in genes encoding this TGF-beta signal, its receptors, and associated Smad signal transduction proteins. daf-3 encodes a Smad protein that is most closely related to mammalian DPC4, and is expressed throughout development in many of the tissues that are remodeled during dauer development. DAF-4, the type II TGF-beta receptor in this pathway, is also expressed in remodeled tissues. These data suggest that the DAF-7 signal from sensory neurons acts as a neuroendocrine signal throughout the body to directly regulate developmental and metabolic shifts in tissues that are remodeled during dauer formation. A full-length functional DAF-3/GFP fusion protein is predominantly cytoplasmic, and this localization is independent of activity of the upstream TGF-beta-related pathway. However, this fusion protein is associated with chromosomes in mitotic cells, suggesting that DAF-3 binds DNA directly or indirectly. DAF-3 transgenes also interfere with dauer formation, perhaps attributable to a dosage effect. A truncated DAF-3/GFP fusion protein that is predominantly nuclear interferes with dauer formation, implying a role for DAF-3 in the nucleus. These data suggest that DAF-7 signal transduction antagonizes or modifies DAF-3 Smad activity in the nucleus to induce reproductive development; when DAF-7 signals are disabled, unmodified DAF-3 Smad activity mediates dauer arrest and its associated metabolic shift. Therefore, daf-3 is unique in that it is antagonized, rather than activated, by a TGF-beta pathway.
来自转化生长因子-β（TGF-β）超家族受体的信号通过Smad蛋白传导至细胞核，Smad蛋白可转录激活靶基因。在秀丽隐杆线虫中，TGF-β相关信号通路的缺陷会导致在 dauer 幼虫阶段出现可逆的发育停滞和代谢转变。daf-3 的无效突变可抑制编码这种TGF-β信号、其受体以及相关Smad信号转导蛋白的基因突变。daf-3 编码一种与哺乳动物 DPC4 最为密切相关的Smad蛋白，并且在 dauer 发育过程中发生重塑的许多组织的整个发育过程中均有表达。该信号通路中的II型TGF-β受体DAF-4也在重塑组织中表达。这些数据表明，来自感觉神经元的DAF-7信号作为一种神经内分泌信号在全身发挥作用，直接调节在 dauer 形成过程中发生重塑的组织中的发育和代谢转变。全长功能性DAF-3/绿色荧光蛋白（GFP）融合蛋白主要位于细胞质中，并且这种定位与上游TGF-β相关信号通路的活性无关。然而，这种融合蛋白在有丝分裂细胞中与染色体相关联，这表明DAF-3直接或间接结合DNA。DAF-3转基因也会干扰 dauer 形成，这可能归因于剂量效应。一种主要位于细胞核中的截短型DAF-3/GFP融合蛋白会干扰 dauer 形成，这意味着DAF-3在细胞核中发挥作用。这些数据表明，DAF-7信号转导拮抗或修饰细胞核中的DAF-3 Smad活性以诱导生殖发育；当DAF-7信号被阻断时，未被修饰的DAF-3 Smad活性介导 dauer 停滞及其相关的代谢转变。因此，daf-3的独特之处在于它被TGF-β信号通路拮抗，而不是激活。
