MORPHOGENESIS OF DIGITS IN THE AVIAN LIMB IS CONTROLLED BY FGFS, TGF-BETA-S, AND NOGGIN THROUGH BMP SIGNALING

In the final stages of limb morphogenesis, autopodial cells leaving th e progress zone differentiate into cartilage or undergo apoptotic cell death, depending on whether they are incorporated into the digital ra ys or interdigital spaces. Most evidence indicates that these two oppo site fates of the autopodial mesoderm are controlled by BIMP signaling . However, the molecular basis for these two distinct actions of BMPs, including the receptors involved in the process, is controversial. In this study we have addressed this question by exploring the presence in the developing autopod of diffusible signals able to modulate BMP f unction and by analyzing the effects of their exogenous administration on the pattern of expression of BMP receptor genes. Our findings show that tgf/beta 2 and noggin genes are expressed in the condensing regi on of the developing digital rays in addition to the well-known distri bution in the autopodial tissues of FGFs (apical ectodermal ridge, AER ) and BMPs (AER, progress zone mesoderm, and interdigital regions). Ex ogenous administration of all the factors causes changes in the expres sion of the bmpR-1b gene which are followed by parallel alterations of the skeletal phenotype: FGFs inhibit the expression of bmpR-1b compat ible with their function in the maintenance of the progress zone mesod erm in an undifferentiated state; and TGE beta s induce the expression of bmpR-1b and promote ectopic chondrogenesis, compatible with a func tion in the establishment of the position of the digital rays. In addi tion we provide evidence for the occurrence of an interactive loop bet ween BMPs and noggin accounting for the spatial distribution of bmpR-1 b which may control the size and shape of the skeletal pieces. In cont rast to the bmpR-1b gene, the bmpR-1a gene is expressed at low levels in the autopodial mesoderm and its expression is not modified by any o f the tested factors regardless of their effects on chondrogenesis or cell death. Finally, the role of BMPs in programmed cell death is conf irmed here by the intense inhibitory effect of noggin on apoptosis, bu t the lack of correlation between changes in the pattern of cell death induced by treatment with the studied factors and the expression of e ither bmpR-1a or bmpR-1b genes suggest that a still-unidentified BMP r eceptor may account for this BMP function. (C) 1998 Academic Press.