FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds.
Anterior-posterior (A-P) patterning of the vertebrate limb is controlled by sonic hedgehog (SHH) signaling, and the precise restriction of Shh expression to the posterior limb bud is essential for its polarizing effect. Fibroblast growth factor (FGF) signaling, a key control of proximal-distal (P-D) limb outgrowth, is known to promote Shh expression in the posterior limb bud. Here, we show that conditional knockout of the FGF-activated transcription factor genes Etv4 and Etv5 in mouse led to ectopic Shh expression in the anterior limb bud and a preaxial polydactyly (PPD) skeletal phenotype. These unexpected results suggest that ETV4 and ETV5 act downstream of FGF signaling to inhibit Shh expression in the anterior limb bud. This finding elucidates a novel aspect of the mechanism coordinating limb development along the A-P and P-D axes.
Zhang
Zhen
Z
Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Verheyden
Jamie M
JM
Hassell
John A
JA
Sun
Xin
X
D000818:Animals; D019521:Body Patterning; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D015536:Down-Regulation; D005091:Exons / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D018878:Limb Buds / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D017689:Polydactyly / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics* / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C540571:Etv4 protein, mouse; C513242:Etv5 protein, mouse; D053823:Hedgehog Proteins; D050783:Proto-Oncogene Proteins c-ets; D017468:Receptors, Fibroblast Growth Factor; D012097:Repressor Proteins; C465570:Shh protein, mouse; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; C045073:Cre recombinase; D019426:Integrases