ROLE OF TGF-BETA-S AND BMPS AS SIGNALS CONTROLLING THE POSITION OF THE DIGITS AND THE AREAS OF INTERDIGITAL CELL-DEATH IN THE DEVELOPING CHICK LIMB AUTOPOD

The establishment of the digital rays and the interdigital spaces in t he developing limb autopod is accompanied by the occurrence of corresp onding domains of expression of TGF beta s and BMPs, This study analyz es whether these coincident events are functionally correlated. The ex periments consisted of local administration of TGF beta-1, TGF beta-2 or BMP-4 by means of heparin or Affi-gel blue beads to the chick limb autopod in the stages preceding the onset of interdigital cell death, When beads bearing either TGF beta-1 or -2 were implanted in the inter digits, the mesodermal cells were diverted from the death program form ing ectopic cartilages or extra digits in a dose- and stage-dependent fashion, This change in the interdigital phenotype was preceded by a p recocious ectopic expression of ck-erg gene around the bead accompanie d by down-regulation of bmp-4, msx-1 and msx-2 gene expression, When B MP-beads were implanted in the interdigital spaces, programmed cell de ath and the freeing of the digits were both accelerated, Implantation of beads bearing BMP-4 at the tip of the growing digits was followed b y digit bifurcation, accompanied by the formation of an ectopic area o f cell death resembling an extra interdigit, both morphologically and molecularly, The death-inducing effect of the BMP beads and the chondr ogenic-inducing effect of the TGF beta beads were antagonized by the i mplantation of an additional bead preabsorbed with FGF-2, which consti tutes a signal characteristic of the progress zone, It is concluded th at the spatial distribution of digital rays and interdigital spaces mi ght be controlled by a patterned distribution of TGF beta s and BMPs i n the mesoderm subjacent to the progress zone.