Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4.
Mice deficient for FgfR2-IIIb were generated by placing translational stop codons and an IRES-LacZ cassette into exon IIIb of FgfR2. Expression of the alternatively spliced receptor isoform, FgfR2-IIIc, was not affected in mice deficient for the IIIb isoform. FgfR2-IIIb(-/-) (lac)(Z) mice survive to term but show dysgenesis of the kidneys, salivary glands, adrenal glands, thymus, pancreas, skin, otic vesicles, glandular stomach, and hair follicles, and agenesis of the lungs, anterior pituitary, thyroid, teeth, and limbs. Detailed analysis of limb development revealed an essential role for FgfR2-IIIb in maintaining the AER. Its absence did not prevent expression of Fgf8, Fgf10, Bmp4, and Msx1, but did prevent induction of Shh and Fgf4, indicating that they are downstream targets of FgfR2-IIIb activation. In the absence of FgfR2-IIIb, extensive apoptosis of the limb bud ectoderm and mesenchyme occurs between E10 and E10.5, providing evidence that Fgfs act primarily as survival factors. We propose that FgfR2-IIIb is not required for limb bud initiation, but is essential for its maintenance and growth.
Revest
J M
JM
Imperial Cancer Research Fund, Lincoln's Inn Fields, London, WC2A 3PX, United Kingdom
Spencer-Dene
B
B
Kerr
K
K
De Moerlooze
L
L
Rosewell
I
I
Dickson
C
C
D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002455:Cell Division; D051526:Fibroblast Growth Factor 10; D051519:Fibroblast Growth Factor 4; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D018878:Limb Buds / Q000502:physiology*; D051957:MSX1 Transcription Factor; D051379:Mice; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C496464:Fgf10 protein, mouse; C496446:Fgf4 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D051519:Fibroblast Growth Factor 4; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D015534:Trans-Activators; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2