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Molecular genetic analysis of glucocorticoid and mineralocorticoid signaling in development and physiological
S A Berger1, T J Cole, W Schmid
1Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
Abstract:
To understand 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. Regulation of the glucocorticoid synthesis via the hypothalamic-pituitary-adrenal axis is perturbed, leading to increased plasma levels of corticosterone and adrenocorticotrophic hormone. Activation 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; no cells capable of adrenaline synthesis can be detected. Mineralocorticoid receptor deficient mice die mainly at day 9/10 after birth. Weightloss 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 and aldosterone are high elevated.
Insights
Disrupting glucocorticoid and mineralocorticoid receptors in mice reveals critical roles in development. Glucocorticoid receptor deficiency causes early death and impaired liver function, while mineralocorticoid receptor loss leads to weight loss and hormonal imbalances.
Area of Science:
- Endocrinology
- Developmental Biology
- 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 characterize the phenotypic consequences of disrupting these receptor genes.
Main Methods:
- Gene targeting was employed to create knockout mouse models for glucocorticoid and mineralocorticoid receptors.
- Phenotypic analysis included survival rates, physiological measurements, and assessment of hormonal regulation.
Main Results:
- Glucocorticoid receptor null mice exhibited perinatal lethality, lung atelectasis, impaired gluconeogenesis, and dysregulated hypothalamic-pituitary-adrenal axis activity.
- Mineralocorticoid receptor null mice displayed postnatal lethality around day 9/10, associated with weight loss, increased hematocrit, and elevated renin and aldosterone levels.
- Adrenal glands in glucocorticoid receptor deficient mice showed hypertrophy/hyperplasia of the cortex but a disorganized, reduced medulla with absent adrenaline synthesis.
Conclusions:
- Glucocorticoid receptors are essential for perinatal survival, lung development, and metabolic regulation.
- Mineralocorticoid receptors are vital for postnatal survival, fluid/electrolyte balance, and cardiovascular homeostasis.
- These findings highlight the indispensable roles of both glucocorticoid and mineralocorticoid signaling pathways in mammalian development and physiology.