RETARDATION OF SKELETAL DEVELOPMENT AND CERVICAL ABNORMALITIES IN TRANSGENIC MICE EXPRESSING A DOMINANT-NEGATIVE RETINOIC ACID RECEPTOR IN CHONDROGENIC CELLS

Skeletal formation is a fundamental element of body patterning and is strictly regulated both temporally and spatially by a variety of molec ules. Among these, retinoic acid (RA) has been shown to be involved in normal skeletal development. However, its pleiotropic effects have ca used difficulty in identifying its crucial target cells and molecular mechanisms for each effect. Development of cartilage primordia is an i mportant process in defining the skeletal structures. To address the r ole of RA in skeletal formation, we have generated mice expressing a d ominant-negative retinoic acid receptor (RAR) in chondrogenic cells by using the type II collagen alpha 1 promoter, and we have analyzed the ir phenotypes. These mice exhibited small cartilage primordia during d evelopment and retarded skeletal formation in both embryonic and postn atal periods. They also showed selective degeneration in their cervica l vertebrae combined with homeotic transformations, but not in their e xtremities. The cervical phenotypes are reminiscent of phenotypes invo lving homeobox genes. We found that the expression of Hoxa-4 was indee d reduced in the cartilage primordia of cervical vertebrae of embryoni c day 12.5 embryos. These observations demonstrate that endogenous RA acts directly on chondrogenic cells to promote skeletal growth in both embryonic and growing periods, and it regulates the proper formation of cervical vertebrae. Furthermore, RA apparently specifies the identi ties of the cervical vertebrae through the regulation of homeobox gene s in the chondrogenic cells. Great similarities of the phenotypes betw een our mice and reported RAR knockout mice revealed that chondrogenic cells are a principal RA target during complex cascades of skeletal d evelopment.