Targeted ablation of pituitary pre-proopiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland

Allen, R.G., Carey, C., Parker, J.D., Mortrud, M.T., Mellon, S.H. and Low, M.J. (1995) Targeted ablation of pituitary pre-proopiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland. Molecular endocrinology, 9 (8), 1005-1016.

Abstract

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). Approximately
98% of the pituitary intermediate lobe melanotropes and anterior lobe
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
gonadotropes was not altered compared with controls, indicating that in
the adult pituitary, POMC products are not required to maintain the
distribution of cell types. As expected, plasma corticosterone levels
were substantially decreased after POMC cell ablation. In situ
hybridization studies showed that the mouse ACTH receptor was expressed
uniformly throughout the adrenal cortex, and RNase protection assays
revealed that the ACTH receptor mRNA decreased after pituitary POMC
cell ablation. Additionally, RNase protection assays showed that
pituitary POMC cell ablation resulted in the decrease of adrenal
p450c11 beta transcripts while p450c11AS (aldosterone synthase) mRNA
levels remained constant. These data demonstrate differential
regulation of steroid pathway-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 refined further to study other
nonmitotic cells.

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