Different degrees of somatotroph ablation compromise pituitary growth hormone cell network structure and other pituitary endocrine cell types

Abstract

We have generated transgenic mice with somatotroph-specific expression of a modified influenza virus ion channel, H37AM2, leading to ablation of GH cells with three levels of severity, dependent on transgene copy number. GH-M2low mice grow normally and have normal-size pituitaries but 40-50% reduction in pituitary GH content in adult animals. GH-M2med mice have male-specific transient growth retardation and a reduction in pituitary GH content by 75% at 42 d and 97% by 100 d. GH-M2high mice are severely dwarfed with undetectable pituitary GH. The GH secretory response of GH-M2low and GH-M2med mice to GH-releasing peptide-6 and GHRH was markedly attenuated. The content of other pituitary hormones was affected depending on transgene copy number: no effect in GH-M2low mice, prolactin and TSH reduced in GH-M2med mice, and all hormones reduced in GH-M2high mice. The effect on non-GH hormone content was associated with increased macrophage invasion of the pituitary. Somatotroph ablation affected GH cell network organization with limited disruption in GH-M2low mice but more severe disruption in GH-M2med mice. The remaining somatotrophs formed tight clusters after puberty, which contrasts with GHRH-M2 mice with a secondary reduction in somatotrophs that do not form clusters. A reduction in pituitary β-catenin staining was correlated with GH-M2 transgene copy number, suggesting M2 expression has an effect on cell-cell communication in somatotrophs and other pituitary cell types. GH-M2 transgenic mice demonstrate that differing degrees of somatotroph ablation lead to correlated secondary effects on cell populations and cellular network organization. Copyright © 2010 by The Endocrine Society.