Role of Rel/NF-κB transcription factors during the outgrowth of the vertebrate limb

The development of the vertebrate limb serves as an amenable system for studying signaling pathways that lead to tissue patterning and proliferation1. Limbs originate as a consequence of a differential growth of cells from the lateral plate mesoderm at specific axial levels2. 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 zone3,4,5,6. The Rel/NF-κB family of transcription factors is induced in response to several signals that lead to cell growth, differentiation, inflammatory responses, apoptosis and neoplastic transformation7. In unstimulated cells, NF-κB is associated in the cytoplasm with an inhibitory protein, I-κB. In response to an external signal, I-κB is phosphorylated, ubiquitinated and degraded, releasing NF-κB to enter the nucleus and activate transcription7. Here we show that Rel/NF-κB genes are expressed in the progress zone of the developing chick limb bud. When theactivity of Rel/NF-κB proteins is blocked by infection with viral vectors that produce transdominant-negative I-κBα proteins, limb outgrowth is arrested. Our results indicate that Rel/NF-κB transcription factors play a role in vertebrate limb development.