Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 andis 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 mi ce deficient for the IIIb isoform. FgfR2-IIIb(-/-) (lacZ) mice survive to t erm but show dysgenesis of the kidneys, salivary glands, adrenal glands, th ymus, 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, indicat ing that they are downstream targets of FgfR2-IIIb activation. In the absen ce of FgfR2-IIIb, extensive apoptosis of the limb bud ectoderm and mesenchy me 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 b ud initiation, but is essential for its maintenance and growth. (C) 2001 Ac ademic Press.