ESTABLISHMENT OF A BMP-4 MORPHOGEN GRADIENT BY LONG-RANGE INHIBITION

Recent work suggests that signaling molecules such as activin are capa ble of acting at long range to establish a morphogen gradient in the a mphibian embryo and that responding cells activate different genes at distinct threshold levels of activin. Other signaling molecules like B MP-4 and Xnr-2 also exert concentration-dependent effects, but these f actors appear to diffuse less freely. This raises the question of whet her gradients of these inducing factors are indeed established, and if so, how they are generated. In this paper we demonstrate directly tha t BMP-4 elicits graded responses in gastrula-stage embryos. We then sh ow that an effective BMP-4 gradient is established not by diffusion of BMP-4 protein but by the long-range effects of two BMP-4 inhibitors, noggin and chordin. This provides a novel mechanism for the establishm ent of a morphogen gradient in vertebrate embryos. (C) 1998 Academic P ress.