Targeted ablation of cells in the pituitary primordia of transgenic mice

Abstract

The various hormones of the anterior pituitary are expressed in a specific temporal and spatial pattern during organogenesis, which is interpreted as a reflection of a temporal pattern of pituitary cytodifferentiation. The first pituitary transcripts detected are from alpha GSU, which encodes the alpha-subunit common to the gonadotropins (FSH and LH) and TSH. TSH beta-subunit transcripts appear several days later but precede transcription of the GH and FSH beta and LH beta-subunit genes. To determine the lineage relationship between the alpha-subunit-expressing cells and the other hormone-producing cells of the anterior pituitary, we have employed the technique of transgene ablation. Transgenic mice were generated that express either the normal diphtheria toxin A chain or a 30-fold less active attenuated version in pituitary gonadotrope and thyrotrope cells. The absence of detectable transcripts for alpha-subunit, TSH beta-subunit, or LH beta-subunit by in situ hybridization confirmed that ablation was complete. In spite of the absence of gonadotropes and thyrotropes, the GH and ACTH-producing cells developed 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 differentiated pituitary cell fates must occur autonomously or before the expression of currently known differentiation markers.