An NF-kappaB and slug regulatory loop active in early vertebrate mesoderm.
BACKGROUND
In both Drosophila and the mouse, the zinc finger transcription factor Snail is required for mesoderm formation; its vertebrate paralog Slug (Snai2) appears to be required for neural crest formation in the chick and the clawed frog Xenopus laevis. Both Slug and Snail act to induce epithelial to mesenchymal transition (EMT) and to suppress apoptosis.


RESULTS
Morpholino-based loss of function studies indicate that Slug is required for the normal expression of both mesodermal and neural crest markers in X. laevis. Both phenotypes are rescued by injection of RNA encoding the anti-apoptotic protein Bcl-xL; Bcl-xL's effects are dependent upon IkappaB kinase-mediated activation of the bipartite transcription factor NF-kappaB. NF-kappaB, in turn, directly up-regulates levels of Slug and Snail RNAs. Slug indirectly up-regulates levels of RNAs encoding the NF-kappaB subunit proteins RelA, Rel2, and Rel3, and directly down-regulates levels of the pro-apopotic Caspase-9 RNA.


CONCLUSIONS
These studies reveal a Slug/Snail-NF-kappaB regulatory circuit, analogous to that present in the early Drosophila embryo, active during mesodermal formation in Xenopus. This is a regulatory interaction of significance both in development and in the course of inflammatory and metastatic disease.
Zhang
Chi
C
Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado, United States of America.
Carl
Timothy F
TF
Trudeau
Evan D
ED
Simmet
Thomas
T
Klymkowsky
Michael W
MW
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494809:BCL2L1 protein, Xenopus; D017931:DNA Primers; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D029867:Xenopus Proteins; D051020:bcl-X Protein; C000604451:sna protein, Drosophila