title: A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth.
abstract: BACKGROUND
  The outgrowth of the vertebrate limb bud is the result of a reciprocal interaction between the mesenchyme and a specialized region of the ectoderm, the apical ectodermal ridge (AER), which overlies it. Signals emanating from the AER act to maintain the underlying mesenchyme, called the progress zone, in a highly proliferative and undifferentiated state. Removal of the AER results in the cessation of limb bud growth, thus causing limb truncation. The best candidates for this AER-derived signal are members of the fibroblast growth factor (FGF) family, in particular FGF-4, which can maintain limb bud outgrowth following removal of the AER. However, FGF-4 is only expressed after considerable outgrowth has occurred and a well-developed limb bud has formed, and then only in the posterior part of the AER. Likewise, the other FGFs studied to date are not candidates for this activity.
  
  
  RESULTS
  We report evidence that a recently identified member of this family, FGF-8, is expressed in the ectoderm of the prospective limb territory prior to morphological outgrowth of the limb bud in both mouse and chick. Thereafter, expression is maintained throughout the AER during limb development. We have produced and purified the FGF-8 protein, and shown that it will substitute for the AER in maintaining limb bud outgrowth in mouse embryos from which the AER has been surgically removed. FGF-8 does not, however, maintain expression of the sonic hedgehog gene.
  
  
  CONCLUSIONS
  These results indicate that FGF-8 is an AER-derived mitogen that stimulates limb bud outgrowth. Moreover, our data suggest that FGF-8 may also be an ectodermally derived mitogen that stimulates the onset of limb bud outgrowth (budding) in the absence of a morphological AER, and indicate the possible involvement of FGF-8 in the establishment of the limb field.
authors.affiliation: Division of Anatomy and Cell Biology, UMDS Guy's Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Mahmood
authors.forename: J
authors.initials: J
authors.lastname: Bresnick
authors.forename: A
authors.initials: A
authors.lastname: Hornbruch
authors.forename: C
authors.initials: C
authors.lastname: Mahony
authors.forename: N
authors.initials: N
authors.lastname: Morton
authors.forename: K
authors.initials: K
authors.lastname: Colquhoun
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.forename: A
authors.initials: A
authors.lastname: Lumsden
authors.forename: C
authors.initials: C
authors.lastname: Dickson
authors.forename: I
authors.initials: I
authors.lastname: Mason
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002642:Chick Embryo; D003001:Cloning, Molecular; D046508:Culture Techniques; D018076:DNA, Complementary; D004475:Ectoderm; D047108:Embryonic Development; D004627:Embryonic Induction / Q000235:genetics / Q000502:physiology*; D005260:Female; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D053823:Hedgehog Proteins; D018878:Limb Buds; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011247:Pregnancy; D011506:Proteins / Q000378:metabolism; D012326:RNA Splicing; D015534:Trans-Activators
chemical_list: D018076:DNA, Complementary; C496457:Fgf8 protein, mouse; D006133:Growth Substances; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D015534:Trans-Activators; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors