Kanegae Y, Tavares A T, Izpisúa Belmonte J C, Verma I M
The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature. 1998 Apr 9;392(6676):611-4. doi: 10.1038/33429.
The development of the vertebrate limb serves as an amenable system for studying signaling pathways that lead to tissue patterning and proliferation. Limbs originate as a consequence of a differential growth of cells from the lateral plate mesoderm at specific axial levels. At the tip of the limb primordia the progress zone, a proliferating group of mesenchymal cells, induces the overlying ectoderm to differentiate into a specialized structure termed the apical ectodermal ridge. Subsequent limb outgrowth requires reciprocal signalling between the ridge and the progress zone. The Rel/NF-kappaB family of transcription factors is induced in response to several signals that lead to cell growth, differentiation, inflammatory responses, apoptosis and neoplastic transformation. In unstimulated cells, NF-kappaB is associated in the cytoplasm with an inhibitory protein, I-kappaB. In response to an external signal, I-kappaB is phosphorylated, ubiquitinated and degraded, releasing NF-kappaB to enter the nucleus and activate transcription. Here we show that Rel/NF-kappaB genes are expressed in the progress zone of the developing chick limb bud. When the activity of Rel/NF-kappaB proteins is blocked by infection with viral vectors that produce transdominant-negative I-kappaBalpha proteins, limb outgrowth is arrested. Our results indicate that Rel/NF-kappaB transcription factors play a role in vertebrate limb development.
脊椎动物肢体的发育是一个便于研究导致组织模式形成和增殖的信号通路的系统。肢体起源于特定轴向水平的侧板中胚层细胞的差异性生长。在肢体原基的顶端，即进展区，一群增殖的间充质细胞诱导上方的外胚层分化为一种称为顶端外胚层嵴的特殊结构。随后的肢体生长需要嵴和进展区之间的相互信号传导。转录因子Rel/NF-κB家族是在响应多种导致细胞生长、分化、炎症反应、细胞凋亡和肿瘤转化的信号时被诱导产生的。在未受刺激的细胞中，NF-κB在细胞质中与一种抑制性蛋白I-κB结合。响应外部信号时，I-κB被磷酸化、泛素化并降解，释放出NF-κB进入细胞核并激活转录。在此我们表明，Rel/NF-κB基因在发育中的鸡肢体芽的进展区表达。当通过感染产生反式显性负性I-κBα蛋白的病毒载体来阻断Rel/NF-κB蛋白的活性时，肢体生长就会停止。我们的结果表明，Rel/NF-κB转录因子在脊椎动物肢体发育中发挥作用。
