Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos.
Initiation and maintenance of signaling centers is a key issue during embryonic development. The apical ectodermal ridge, a specialized epithelial structure and source of Fgf8, is a pivotal signaling center for limb outgrowth. We show that two closely related buttonhead-like zinc-finger transcription factors, Sp8 and Sp9, are expressed in the AER, and regulate Fgf8 expression and limb outgrowth. Embryological and genetic analyses have revealed that Sp8 and Sp9 are ectodermal targets of Fgf10 signaling from the mesenchyme. We also found that Wnt/beta-catenin signaling positively regulates Sp8, but not Sp9. Overexpression functional analyses in chick unveiled their role as positive regulators of Fgf8 expression. Moreover, a dominant-negative approach in chick and knockdown analysis with morpholinos in zebrafish revealed their requirement for Fgf8 expression and limb outgrowth, and further indicate that they have a coordinated action on Fgf8 expression. Our study demonstrates that Sp8 and Sp9, via Fgf8, are involved in mediating the actions of Fgf10 and Wnt/beta-catenin signaling during vertebrate limb outgrowth.
Kawakami
Yasuhiko
Y
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA.
Esteban
Concepción Rodríguez
CR
Matsui
Takaaki
T
Rodríguez-León
Joaquín
J
Kato
Shigeaki
S
Izpisúa Belmonte
Juan Carlos
JC
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002642:Chick Embryo; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D019143:Evolution, Molecular; D005121:Extremities / Q000196:embryology*; D051526:Fibroblast Growth Factor 10; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051153:Wnt Proteins; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C496464:Fgf10 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D011518:Proto-Oncogene Proteins; C490035:Sp8 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors