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Recent work suggests that signaling molecules such as activin are capable of acting at long range to establish a morphogen gradient in the amphibian embryo and that responding cells activate different genes at distinct threshold levels of activin. Other signaling molecules like BMP-4 and Xnr-2 also exert concentration-dependent effects, but these factors appear to diffuse less freely. This raises the question of whether gradients of these inducing factors are indeed established, and if so, how they are generated. In this paper we demonstrate directly that BMP-4 elicits graded responses in gastrula-stage embryos. We then show 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 establishment of a morphogen gradient in vertebrate embryos.
FIG. 1. Myf-5 expression at (A) stage 10, (B) stage 10.25, (C) stage 10.5, and (D) stage 11.5. Overexpression of BMP-4 results in (E and
F) complete suppression of Myf-5 expression or, in 3 of 16 embryos (G), in partial suppression with residual expression (arrow) centered
over the dorsal blastopore lip. (H and I) Clones of cells expressing BMP-4 within the lateral marginal zone (marked red in H and light
blue in I) suppress Myf-5 expression over a distance of 3–5 cells (arrows). (J) A small clone of BMP-4-producing cells within the dorsal
marginal zone causes ectopic induction of Myf-5 in a domain 3–5 cells away from the BMP-4 source. (K) A flat mount of the embryo
shown in J. The arrow indicates a region between the BMP-4 source and the ectopic Myf-5 expression where no Myf-5 transcripts are
detected, presumably because the local BMP-4 concentration is too high.
FIG. 2. (A–F) Activation of Myf-5 expression in tissue recombinants comprising noggin- or chordin-injected animal caps and ventral
marginal zone explants. Lineage tracing analyses show that the Myf-5 transcripts are restricted to the ventral marginal zone portion of
the tissue recombinants (data not shown). (A and B) Induction of Myf-5 expression in noggin- and chordin-expressing animal cap:ventral
marginal zone recombinants. The recombinants were assembled at the early gastrula stage and cultured for 6 h. (C–E) Noggin-expressing
animal caps cause activation of Myf-5 expression (denoted by white arrows) within 3 h (E) of combination with ventral marginal zone tissue. No Myf-5 transcripts are detected at 1 or 2 h (C and D). Control ventral marginal zones do not express Myf-5 (F). (G–P) Myf-5
expression induced by the direct and long-range actions of noggin in early Xenopus gastrulae. Cells expressing noggin (G–N) or a truncated
BMP receptor (O and P) are marked red and Myf-5 expression appears dark purple. (G and H) Vegetal views of preparations in which lowlevel
noggin-expressing clones (100 pg RNA) induce a domain of Myf-5 expression in the ventral marginal zone. (I and J) Flat-mount
preparations demonstrating the short-range non-cell-autonomous induction of Myf-5 in response to the effects of low levels of noggin.
The black arrow in I denotes endogenous Myf-5 expression. Ectopic Myf-5 expression is detected both within the noggin-expressing cells
and just outside the expression domain (J). (K–N) A high-level noggin source (1 ng RNA) induces ectopic Myf-5 expression over many
cell diameters. A vegetal view of a representative embryo demonstrates that the long-range actions of noggin can spread over at least onequarter
of the embryo (K) The black arrow points to the domain of endogenous Myf-5 expression. (L) A low-magnification view of a flat
mount of the embryo in K. The ectopic noggin expression domain was separated from the rest of the embryo. Vegetal is toward the top.
(M and N) Higher magnifications of the same flat mount (M) or another example (N). Induction of Myf-5 in response to noggin is only
detected within the marginal zone. (O and P) Localized expression of a truncated BMP receptor in the ventral marginal zone causes cellautonomous
ectopic expression of Myf-5. Whole-embryo (O) and flat-mount (P) preparations are shown.
