INHIBITION OF NF-KAPPA-B ACTIVITY RESULTS IN DISRUPTION OF THE APICALECTODERMAL RIDGE AND ABERRANT LIMB MORPHOGENESIS

In Drosophila, the Dorsal protein establishes the embryonic dorso-vent ral axis during development(1), Here we show that the vertebrate homol ogue of Dorsal, nuclear factor-kappa B (NF-kappa B), is vital for the formation of the proximo-distal organizer of the developing limb bud, the apical ectodermal ridge (AER). Transcription of the NF-kappa B pro to-oncogene c-rel is regulated, in part, during morphogenesis of the l imb bud by AER-derived signals such as fibroblast growth factors. Inte rruption of NF-kappa B activity using viral-mediated delivery of an in hibitor results in a highly dysmorphic AER, reduction in overall limb size, loss of distal elements and reversal in the direction of limb ou tgrowth. Furthermore, inhibition of NF-kappa B activity in limb mesenc hyme leads to a reduction in expression of Sonic hedgehog and Twist bu t derepresses expression of the bone morphogenetic protein-4 gene. The se results are the first evidence that vertebrate NF-kappa B proteins act to transmit growth factor signals between the ectoderm and the und erlying mesenchyme during embryonic limb formation.