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Development 129, 5289-5300 (2002)
Copyright © 2002 The Company of Biologists Limited

growth arrest specific gene 1 acts as a region-specific mediator of the Fgf10/Fgf8 regulatory loop in the limb

Ying Liu1, Chunqiao Liu1, Yoshihiko Yamada2 and Chen-Ming Fan1,*

1 Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland 21210, USA
2 Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA

* Author for correspondence (e-mail: fan{at}ciwemb.edu)

Accepted 21 August 2002

Proximal-to-distal growth of the embryonic limbs requires Fgf10 in the mesenchyme to activate Fgf8 in the apical ectodermal ridge (AER), which in turn promotes mesenchymal outgrowth. We show here that the growth arrest specific gene 1 (Gas1) is required in the mesenchyme for the normal regulation of Fgf10/Fgf8. Gas1 mutant limbs have defects in the proliferation of the AER and the mesenchyme and develop with small autopods, missing phalanges and anterior digit syndactyly. At the molecular level, Fgf10 expression at the distal tip mesenchyme immediately underneath the AER is preferentially affected in the mutant limb, coinciding with the loss of Fgf8 expression in the AER. To test whether FGF10 deficiency is an underlying cause of the Gas1 mutant phenotype, we employed a limb culture system in conjunction with microinjection of recombinant proteins. In this system, FGF10 but not FGF8 protein injected into the mutant distal tip mesenchyme restores Fgf8 expression in the AER. Our data provide evidence that Gas1 acts to maintain high levels of FGF10 at the tip mesenchyme and support the proposal that Fgf10 expression in this region is crucial for maintaining Fgf8 expression in the AER.

Key words: Gas1, Fgf8, Fgf10, Limb, Growth, Apical ectodermal ridge, Mouse






© The Company of Biologists Ltd 2002