Development of the mandibular skeleton in the embryonic chick as evaluated using the DNA-inhibiting agent...

Mandibular development was examined in embryonic chicks following administration of 5-fluoro-2'-deoxyuridine (FUDR, 0.001-1.0 microgram/egg), an inhibitor of both DNA synthesis and of cell division. FUDR was injected in ovo at one of three developmental stages corresponding to 1) the migration of mandible-destined, midbrain-level neural crest cells (Hamburger and Hamilton [H.H.] stage 10); 2) midway through the epithelial-mesenchymal interaction required to initiate mandibular osteogenesis (H.H. stage 22), which is also after the epithelial-neural crest cell interaction required for the initiation of chondrogenesis in Meckel's cartilage; and 3) when prechondroblasts of Meckel's cartilage are beginning to differentiate (H.H. stage 25). Micromelia was induced following the administration of FUDR at either H.H. stages 22 or 25 but not when FUDR was given at H.H. stage 10. Although the micromelic mandibles were shorter than normal, Meckel's cartilage and the mandibular membrane bones both differentiated and grew along the full proximodistal length of the shortened mandibles. In contrast to the situation previously described by Ferguson for alligator embryos exposed to FUDR, the migration of neural crest cells in the embryonic chick was not inhibited by FUDR. In contrast to the situation previously described for rat embryos exposed to FUDR, differentiation of Meckel's cartilage was not inhibited in embryonic chicks exposed to FUDR. Differentiation of the membrane bones was also normal following either in ovo administration of FUDR or when mandibular processes were maintained in FUDR in vitro. Therefore, FUDR does not produce micromelia in the embryonic chick by interfering with the epithelial-mesenchymal/neural crest cell interactions, which are prerequisites or differentiation of cartilage or bone, nor by inhibiting the differentiation of chondrogenic or osteogenic mesenchymal cells after completion of these tissue interactions. Neither did the growth-inhibiting action of FUDR result from an inhibition of growth of Meckel's cartilage during the several days following initial chondrogenic differentiation. Rather, subsequent growth of the entire mandibular process was delayed. This mechanism of action differs from that in the alligator embryo, in which FUDR inhibits mandibular growth by removing mandible-destined, migrating neural crest cells, and in the rat, in which FUDR inhibits the differentiation of Meckel's cartilage but catch-up growth restores growth of the mandible to normal.