Different degrees of somatotroph ablation compromise pituitary growth hormone cell network structure and other pituitary endocrine cell types.
We have generated transgenic mice with somatotroph-specific expression of a modified influenza virus ion channel, (H37A)M2, leading to ablation of GH cells with three levels of severity, dependent on transgene copy number. GH-M2(low) mice grow normally and have normal-size pituitaries but 40-50% reduction in pituitary GH content in adult animals. GH-M2(med) 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-M2(high) mice are severely dwarfed with undetectable pituitary GH. The GH secretory response of GH-M2(low) and GH-M2(med) 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-M2(low) mice, prolactin and TSH reduced in GH-M2(med) mice, and all hormones reduced in GH-M2(high) 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-M2(low) mice but more severe disruption in GH-M2(med) 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 beta-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.
Waite
Eleanor
E
Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
Lafont
Chrystel
C
Carmignac
Danielle
D
Chauvet
Norbert
N
Coutry
Nathalie
N
Christian
Helen
H
Robinson
Iain
I
Mollard
Patrice
P
Le Tissier
Paul
P
D000818:Animals; D002450:Cell Communication / Q000235:genetics* / Q000502:physiology; D002452:Cell Count; D004393:Dwarfism, Pituitary / Q000209:etiology / Q000235:genetics; D055098:Endocrine Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage / Q000502:physiology; D041722:Genes, Transgenic, Suicide / Q000502:physiology; D019382:Human Growth Hormone / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009929:Organ Size / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D010902:Pituitary Gland / Q000166:cytology* / Q000378:metabolism; D052683:Somatotrophs / Q000166:cytology* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics; D000086082:Viroporin Proteins
D019382:Human Growth Hormone; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins