Control of digit formation by activin signalling

Major advances in the genetics of vertebrate limb development have been obt ained in recent years, However, the nature of the signals which trigger dif ferentiation of the mesoderm to form the limb skeleton remains elusive. Pre viously, we have obtained evidence for a role of TGF beta 2 in digit format ion, Here, we show that activins A and B and/or AB are also signals involve d in digit skeletogenesis. activin PA gene expression correlates with the i nitiation of digit chondrogenesis while activin PB is expressed coincidentl y with the formation of the last phalanx of each digit. Exogenous administr ation of activins A, B or AB into the interdigital regions induces the form ation of extra digits, follistatin, a natural antagonist of activins, is ex pressed, under the control of activin, peripherally to the digit chondrogen ic aggregates marking the prospective tendinous blastemas, Exogenous applic ation of follistatin blocks physiological and activin-induced digit formati on. Evidence for a close interaction between activins and other signalling molecules, such as BMPs and FGFs, operating at the distal tip of the limb a t these stages is also provided, Chondrogenesis by activins is mediated by BMPs through the regulation of the BMP receptor bmpR-1b and in turn activin expression is upregulated by BMP signalling. In addition, AER hyperactivit y secondary to Wnt3A misexpression or local administration of FGFs, inhibit s activin expression. In correlation with the restricted expression of acti vins in the course of digit formation, neither activin nor follistatin trea tment affects the development of the skeletal components of the stylopod or zeugopod indicating that the formation of the limb skeleton is regulated b y segment-specific chondrogenic signals.