Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos

Yasuhiko Kawakami, Concepción Rodríguez-Esteban, Takaaki Matsui, Joaquín Rodríguez-León, Shigeaki Kato, Juan Carlos Izpisúa Belmonte*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

125 Scopus citations


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/β -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/β-catenin signaling during vertebrate limb outgrowth.

Original languageEnglish (US)
Pages (from-to)4763-4774
Number of pages12
Issue number19
StatePublished - Oct 2004


  • Apical ectodermal ridge
  • Fgf10
  • Fgf8
  • Sp transcription factor
  • Vertebrate limb
  • Wnt

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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