title: Growth arrest specific gene 1 acts as a region-specific mediator of the Fgf10/Fgf8 regulatory loop in the limb.
abstract: Proximal-to-distal growth of the embryonic limbs requires Fgf10 in the mesenchyme to activate Fgf8 in the apical ectodermal ridge (AER), which in turn promotes mesenchymal outgrowth. We show here that the growth arrest specific gene 1 (Gas1) is required in the mesenchyme for the normal regulation of Fgf10/Fgf8. Gas1 mutant limbs have defects in the proliferation of the AER and the mesenchyme and develop with small autopods, missing phalanges and anterior digit syndactyly. At the molecular level, Fgf10 expression at the distal tip mesenchyme immediately underneath the AER is preferentially affected in the mutant limb, coinciding with the loss of Fgf8 expression in the AER. To test whether FGF10 deficiency is an underlying cause of the Gas1 mutant phenotype, we employed a limb culture system in conjunction with microinjection of recombinant proteins. In this system, FGF10 but not FGF8 protein injected into the mutant distal tip mesenchyme restores Fgf8 expression in the AER. Our data provide evidence that Gas1 acts to maintain high levels of FGF10 at the tip mesenchyme and support the proposal that Fgf10 expression in this region is crucial for maintaining Fgf8 expression in the AER.
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland 21210, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Chunqiao
authors.initials: C
authors.lastname: Liu
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Fan
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D004475:Ectoderm / Q000166:cytology; D005121:Extremities / Q000196:embryology*; D005260:Female; D051526:Fibroblast Growth Factor 10; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D058851:GPI-Linked Proteins; D018507:Gene Expression Regulation, Developmental; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm; D051379:Mice; D008817:Mice, Mutant Strains; D008845:Microinjections; D009154:Mutation
chemical_list: D018797:Cell Cycle Proteins; C496464:Fgf10 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D008565:Membrane Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors