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Analysis of glucocorticoid and mineralocorticoid signalling by gene targeting
1Division Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
Abstract:
To get a better understanding of the role of glucocorticoid and mineralocorticoid signalling during development and in whole animal physiology, we have disrupted the mouse glucocorticoid and mineralocorticoid receptor gene by gene targeting. Most of the mice with a disrupted glucocorticoid receptor gene die within the first hours after birth due to severe lung atelectasis. Perinatal induction of gluconeogenic enzymes in the liver is impaired. Feed back control of the glucocorticoid synthesis via the hypothalamic-pituitary-adrenal axis is perturbed leading to increased plasma levels of corticosterone and adrenocorticotrophic hormone. Increased activity of the hypothalamic-pituitary-adrenal axis results in extensive hypertrophy and hyperplasia of the cortical zones of the adrenal and induction of genes involved in steroid biosynthesis. The adrenal medulla is disorganized and severely reduced in size; cells capable of adrenaline synthesis are missing. Mineralocorticoid receptor deficient mice die around day 10 after birth. Weight loss precedes death of homozygous mutant mice and is correlated with an increase in the haematocrit. As a consequence of this mutation plasma levels of renin, angiotensin II, and aldosterone are highly elevated.
Insights
Disrupting glucocorticoid and mineralocorticoid receptor genes in mice reveals critical roles in development and physiology. Glucocorticoid receptor disruption causes early death and impaired liver function, while mineralocorticoid receptor deficiency leads to weight loss and hormonal imbalances.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Genetics
Background:
- Glucocorticoid and mineralocorticoid signaling are crucial for physiological homeostasis and development.
- Understanding the specific roles of these receptors requires targeted genetic investigation.
Purpose of the Study:
- To elucidate the functions of glucocorticoid and mineralocorticoid receptors during mouse development and physiology.
- To investigate the consequences of disrupting these receptor genes.
Main Methods:
- Gene targeting was employed to create mouse models with disrupted glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) genes.
- Phenotypic analysis of mutant mice included survival rates, organ morphology, and plasma hormone level measurements.
Main Results:
- GR-deficient mice exhibited perinatal lethality, lung atelectasis, impaired gluconeogenesis, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis with adrenal abnormalities.
- MR-deficient mice showed postnatal lethality around day 10, associated with weight loss, increased hematocrit, and elevated renin-angiotensin-aldosterone system (RAAS) components.
Conclusions:
- Glucocorticoid signaling is essential for immediate postnatal survival, lung development, and HPA axis regulation.
- Mineralocorticoid signaling is vital for postnatal growth and maintaining fluid/electrolyte balance, with MR deficiency severely impacting the RAAS.