TARGETED ABLATION OF CELLS IN THE PITUITARY PRIMORDIA OF TRANSGENIC MICE

The various hormones of the anterior pituitary are expressed in a spec ific temporal and spatial pattern during organogenesis, which is inter preted as a reflection of a temporal pattern of pituitary cytodifferen tiation. The first pituitary transcripts detected are from alpha GSU, which encodes the alpha-subunit common to the gonadotropins (FSH and L H) and TSH. TSH beta-subunit transcripts appear several days later but precede transcription of the GH and FSH beta and LH beta-subunit gene s. To determine the lineage relationship between the alpha-subunit-exp ressing cells and the other hormone-producing cells of the anterior pi tuitary, we have employed the technique of transgene ablation. Transge nic mice were generated that express either the normal diphtheria toxi n A chain or a 30-fold less active attenuated version in pituitary gon adotrope and thyrotrope cells. The absence of detectable transcripts f or alpha-subunit, TSH beta-subunit, or LH beta-subunit by in situ hybr idization confirmed that ablation was complete. In spite of the absenc e of gonadotropes and thyrotropes, the GH and ACTH-producing cells dev eloped normally. These results imply that although thyrotropes appear early in pituitary development, they are not obligate intermediates in the developmental pathway. Instead, commitment to individual differen tiated pituitary cell fates must occur autonomously or before the expr ession of currently known differentiation markers.