Document Detail

Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning.
MedLine Citation:
PMID:  18449196     Owner:  NLM     Status:  MEDLINE    
Half a century ago, the apical ectodermal ridge (AER) at the distal tip of the tetrapod limb bud was shown to produce signals necessary for development along the proximal-distal (P-D) axis, but how these signals influence limb patterning is still much debated. Fibroblast growth factor (FGF) gene family members are key AER-derived signals, with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER. Here we demonstrate that mouse limbs lacking Fgf4, Fgf9 and Fgf17 have normal skeletal pattern, indicating that Fgf8 is sufficient among AER-FGFs to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when we also removed different combinations of the other AER-FGF genes, we obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P-D-patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the long-standing hypothesis that AER-FGF signalling is permissive rather than instructive for limb patterning. We discuss how a two-signal model for P-D patterning can be integrated with the concept of early specification to explain the genetic data presented here.
Francesca V Mariani; Christina P Ahn; Gail R Martin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-04-30
Journal Detail:
Title:  Nature     Volume:  453     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-15     Completed Date:  2008-06-24     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  401-5     Citation Subset:  IM    
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MeSH Terms
Body Patterning / genetics*,  physiology*
Bone and Bones / embryology,  metabolism
Cell Survival
Fibroblast Growth Factor 8 / deficiency,  genetics,  metabolism*
Fibroblast Growth Factors / deficiency,  genetics,  metabolism*
Homeodomain Proteins / genetics
Limb Buds / cytology,  embryology*,  metabolism
Neoplasm Proteins / genetics
Organ Size
Signal Transduction
Grant Support
F32 HD008696/HD/NICHD NIH HHS; F32 HD008696-01/HD/NICHD NIH HHS; F32 HD008696-02/HD/NICHD NIH HHS; F32 HD008696-03/HD/NICHD NIH HHS; R01 HD034380/HD/NICHD NIH HHS; R01 HD034380-05/HD/NICHD NIH HHS; R01 HD034380-06/HD/NICHD NIH HHS; R01 HD034380-07/HD/NICHD NIH HHS; R01 HD034380-08/HD/NICHD NIH HHS; R01 HD034380-09/HD/NICHD NIH HHS; R01 HD34380/HD/NICHD NIH HHS
Reg. No./Substance:
0/Fgf8 protein, mouse; 0/Homeodomain Proteins; 0/Neoplasm Proteins; 0/myeloid ecotropic viral integration site 1 protein; 148997-75-5/Fibroblast Growth Factor 8; 62031-54-3/Fibroblast Growth Factors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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