Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis.
In Drosophila, the Dorsal protein establishes the embryonic dorso-ventral axis during development. Here we show that the vertebrate homologue of Dorsal, nuclear factor-kappa B (NF-kappaB), is vital for the formation of the proximo-distal organizer of the developing limb bud, the apical ectodermal ridge (AER). Transcription of the NF-kappaB proto-oncogene c-rel is regulated, in part, during morphogenesis of the limb bud by AER-derived signals such as fibroblast growth factors. Interruption of NF-kappaB activity using viral-mediated delivery of an inhibitor results in a highly dysmorphic AER, reduction in overall limb size, loss of distal elements and reversal in the direction of limb outgrowth. Furthermore, inhibition of NF-kappaB activity in limb mesenchyme leads to a reduction in expression of Sonic hedgehog and Twist but derepresses expression of the bone morphogenetic protein-4 gene. These results are the first evidence that vertebrate NF-kappaB proteins act to transmit growth factor signals between the ectoderm and the underlying mesenchyme during embryonic limb formation.
Bushdid
P B
PB
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
Brantley
D M
DM
Yull
F E
FE
Blaeuer
G L
GL
Hoffman
L H
LH
Niswander
L
L
Kerr
L D
LD
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002642:Chick Embryo; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004627:Embryonic Induction; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D053823:Hedgehog Proteins; D020672:I-kappa B Proteins; D018878:Limb Buds / Q000196:embryology*; D009024:Morphogenesis / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators
D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D015534:Trans-Activators; D000072000:NF-KappaB Inhibitor alpha