Skeletal morphogenesis: comparative effects of a mutant gene and a teratogen

As a teratogenic agent retinoic acid (RA) produces severe limb reduction defects if administered at a certain stage of embryonic development. In vitro, RA is able to prevent chondrogenesis and this inhibitory effect is accompanied by the absence of cartilage specific proteoglycans in treated cultures. Such an effect is ruled out as a direct causative factor in teratogenesis for two reasons. First, the limbs of treated embryos show extensive chondrogenesis and this cartilage is normal as far as the expression of biochemical markers of differentiation are concerned. Second, the morphogenetic effects of a mutant gene, cmd, where there is a functional deficit of the proteoglycan core protein are very different from those associated with RA-induced teratogenesis. The differences between the two are not wholly reconciled by the fact that the effects of the mutant gene are cumulative and progressive while those of the RA insult are transitory. There are a number of developmental events which are, however, altered by RA in the mesenchymal cells of the early limb bud such as cell proliferation, cell death, and hyaluronic acid metabolism. Not only any one or more of these factors may secondarily inhibit chondrogenesis but, more importantly, may also have a number of other consequences in the developing embryo. Since a number of cell types besides mesenchymal cells respond to RA by altering their pattern of differentiation, it is conceivable that some fundamental molecular step in the process of differentiation provides a target for its action. In a recent review, Sporn and Roberts (1983) have suggested that to be compatible with the wide ranging effects of retinoids documented so far, any hypothesis put forward for its molecular mechanism of action must include a role in gene expression. No experimental work has yet directly addressed how retinoids might modify gene expression. We believe that along with teratocarcinoma stem cell lines, the use of retinoids as selective teratogens may open up another avenue in search of molecular mechanisms of cell differentiation.