FGF Signaling and Digit Formation

Abstract

Individual digits contain defined numbers of phalanges (the bones of the fingers and toes) with characteristic lengths and shapes. Sonic hedgehog (Shh) signaling affects phalange number and digit morphology; however, the underlying molecular mechanisms remain poorly understood. Sanz-Ezquerro and Tickle implanted Shh-soaked microcarrier beads in the interdigital spaces of developing chick legs and wings and discovered that only beads located near the apical ectodermal ridge [which mediates limb bud outgrowth through fibroblast growth factor 8 (FGF8)] elicited the production of additional phalanges. The authors used in situ hybridization to show that Shh stimulated prolonged expression of apical ridge Fgf8. Coimplanted beads soaked in an FGF receptor tyrosine kinase inhibitor (SU5402) inhibited the production of additional phalanges. The additional phalanges were generated through elongation and segmentation of the penultimate phalange, whereas more proximal phalanges did not elongate, and digit tips were generally normal. FGF-soaked beads implanted at the end of a digit inhibited formation of the digit tip, whereas inhibition of FGF signaling (with SU5402 or PD184352, a mitogen-associated protein kinase kinase inhibitor) led to premature tip formation and shorter digits. Thus, elongation and generation of the terminal phalange appear to require high concentrations of FGF, whereas tip formation appears to depend on the termination of FGF signaling. These data suggest that development of the terminal phalange and formation of the digit tip may involve mechanisms distinct from those involved in the development of the more proximal phalanges. J. J. Sanz-Ezquerro, C. Tickle, Fgf signaling controls the number of phalanges and tip formation in developing digits. Current Biol. 13 , 1830-1836 (2003). [Online Journal]