S. Pizette et L. Niswander, BMPs negatively regulate structure and function of the limb apical ectodermal ridge, DEVELOPMENT, 126(5), 1999, pp. 883-894
The apical ectodermal ridge (AER), a transient specialized epithelium at th
e distal limb tip, is essential for vertebrate embryonic limb outgrowth alo
ng the proximodistal axis. Among all the molecules expressed in the AER, on
ly the Fibroblast Growth Factors (FGFs) have been shown to substitute for i
ts function in limb outgrowth. After specification of the skeletal progenit
ors is complete, the AER regresses, having fulfilled its function. However,
the cellular processes underlying AER regression remain largely unclear, a
nd the molecular ones, totally unknown.
Members of the Bone Morphogenetic Protein (BMP) family are expressed in the
AER throughout its life and in the mesenchyme, Our studies using misexpres
sion of Noggin, a BMP inhibitor, reveal an unsuspected role for BMPs in the
negative regulation of Fgf expression and AER function. We find that BMPs
limit limb outgrowth by promoting AER regression, as BMP inhibition results
in persistence of the AER, prolonged Fgf expression and excess soft-tissue
growth. In addition, the Noggin misexpression studies uncover an earlier r
ole for BMPs in repression of AER function. Noggin overexpression results i
n extension of the AER anteriorly and loss of AER asymmetry. We show that o
verall the AER becomes taller, and its anterior half becomes more similar t
o a normal posterior AER, In addition, Fgf4 transcripts, which are usually
restricted to the posterior half of the AER, are now also expressed anterio
rly. Moreover, ectopicFgf4 expression is induced independently of Sonic Hed
gehog, contrary to current models of Fgf4 regulation in the limb. Our studi
es also provide insight into the activity of the hypothesized apical ectode
rmal maintenance factor (AEMF), which is thought to maintain the tall shape
of the posterior part of the AER, Our work shows that the AER is negativel
y regulated by BMP.