Is chordin a long-range- or short-range-acting factor? Roles for BMP1-related metalloproteases in chordin and BMP4 autofeedback loop regulation

Diffusible morphogen models have been used widely to explain regional speci fication of tissues and body axes during animal development. The three-sign al model for patterning the dorsal-ventral axis of the amphibian embryo pro poses, in part, that a factor(s) secreted from Spemann's organizer is respo nsible for converting lateral marginal zone into more dorsal cell fates. We examine the possibility that chordin, a secreted inhibitor of bone morphog enetic protein (BMP) signaling and candidate "dorsalizing signal," is a lon g-range-acting factor. We show that chordin can, when overexpressed, act di rectly over distances of at least 450 mu m in the early Xenopus embryo to c reate a gradient of BMP signaling. However, since lower levels of chordin c an still induce secondary axes and these amounts of chordin act only locall y to inhibit a BMP target gene, we suggest that chordin likely acts as a sh ort-range signal in vivo. Furthermore, BMP1, a secreted metalloprotease tha t cleaves chordin protein in vitro, inhibits chordin's axis-inducing effect s, suggesting that BMP1 functions to negatively regulate chordin's action i n vivo. A dominant-negative mutant BMP1 blocks the in vitro cleavage of cho rdin protein by wild-type BMP1 and induces secondary axes when injected ven trally. We argue that BMP1 and Xolloid are probably functionally redundant metalloproteases and may have two roles in the early Xenopus embryo. One ro le may be to inhibit the action of low-level chordin protein expressed thro ughout the entire embryo and a possible second role may be to inhibit activ ation of a juxtacrine cell relay, thereby confining chordin's action to the organizer region preventing chordin from functioning as a long-range-actin g factor. (C) 2000 Academic Press.