A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth.
Signals from the apical ectodermal ridge (AER) of the developing vertebrate limb, including fibroblast growth factor-8 (FGF-8), can maintain limb mesenchymal cells in a proliferative state. We report here that a specific CD44 splice variant is crucial for the proliferation of these mesenchymal cells. Epitopes carried by this variant colocalize temporally and spatially with FGF-8 in the AER throughout early limb development. A splice variant containing the same sequences expressed on model cells binds both FGF-4 and FGF-8 and stimulates mesenchymal cells in vitro. When applied to the AER, an antibody against a specific CD44 epitope blocks FGF presentation and inhibits limb outgrowth. Therefore, CD44 is necessary for limb development and functions in a novel growth factor presentation mechanism likely relevant in other physiological and pathological situations where a cell surface protein presents a signaling molecule to a neighboring cell.
Sherman
L
L
Forschungszentrum Karlsruhe, Institut für Genetik, D-76021 Karlsruhe, Germany.
Wainwright
D
D
Ponta
H
H
Herrlich
P
P
D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005121:Extremities / Q000196:embryology; D051519:Fibroblast Growth Factor 4; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000276:immunology / Q000378:metabolism*; D006133:Growth Substances / Q000276:immunology / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D051381:Rats
C496447:Fgf4 protein, rat; C496458:Fgf8 protein, rat; D051519:Fibroblast Growth Factor 4; D006133:Growth Substances; D018960:Hyaluronan Receptors; D011518:Proto-Oncogene Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors