Role of Rel/NF-kappaB 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 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.