TARGETED ABLATION OF PITUITARY PRE-PROOPIOMELANOCORTIN CELLS BY HERPES-SIMPLEX VIRUS-1 THYMIDINE KINASE DIFFERENTIALLY REGULATES MESSENGER-RNAS ENCODING THE ADRENOCORTICOTROPIN RECEPTOR AND ALDOSTERONE SYNTHASE IN THE MOUSE ADRENAL-GLAND

We have produced and characterized lines of transgenic mice expressing a fusion gene composed of the pituitary expression-specific promoter region of the POMC gene, driving the herpes simplex viral-1 thymidine kinase. Adult mice were treated with the antiherpes agent ganciclovir at 70 mg/kg body weight (ip, twice daily for 10-12 days). Approximatel y 98% of the pituitary intermediate lobe melanotropes and anterior lob e corticotropes were ablated as determined by immunocytochemistry and RIA specific for the POMC-derived peptides, ACTH, beta-endorphin, and alpha-MSH. The number of lactotropes, somatotropes, thyrotropes, and g onadotropes was not altered compared with controls, indicating that in the adult pituitary, POMC products are not required to maintain the d istribution of cell types. As expected, plasma corticosterone levels w ere substantially decreased after POMC cell ablation. In situ hybridiz ation studies showed that the mouse ACTH receptor was expressed unifor mly throughout the adrenal cortex, and RNase protection assays reveale d that the ACTH receptor mRNA decreased after pituitary POMC cell abla tion. Additionally, RNase protection assays showed that pituitary POMC cell ablation resulted in the decrease of adrenal p450c11 beta transc ripts while p450c11AS (aldosterone synthase) mRNA levels remained cons tant. These data demonstrate differential regulation of steroid pathwa y-specific enzymes by POMC products. Our results also suggest that the thymidine kinase cell obliteration technique may not be dependent on cell division as a prerequisite for cytotoxicity, thus supporting the idea that targeted molecular ablation using cell- and tissue-specific promoter sequences to drive viral thymidine kinase expression can be r efined further to study other nonmitotic cells.