Aged PROP1 deficient dwarf mice maintain ACTH production

PLoS One. 2011;6(12):e28355. doi: 10.1371/journal.pone.0028355. Epub 2011 Dec 1.

Abstract

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1(null) (Prop1(-/-)) and the Ames dwarf (Prop1(df/df)) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenocorticotropic Hormone / blood*
  • Aging / pathology*
  • Animals
  • Blood Glucose / metabolism
  • Corticosterone / blood
  • Dwarfism / genetics*
  • Female
  • Growth Hormone / deficiency*
  • Homeodomain Proteins / physiology*
  • Homozygote
  • Hypopituitarism / genetics
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / genetics
  • Phenotype
  • Prolactin / deficiency
  • Radioimmunoassay

Substances

  • Blood Glucose
  • Homeodomain Proteins
  • Prophet of Pit-1 protein
  • Adrenocorticotropic Hormone
  • Prolactin
  • Growth Hormone
  • Corticosterone