ACTH signalling and adrenal development: lessons from mouse models

Area of Science:

• Endocrinology and Molecular Biology
• Adrenal Gland Physiology
• Genetics and Disease Modeling

Background:

• The melanocortin-2-receptor (MC2R), or ACTH receptor, is vital for the hypothalamic-pituitary-adrenal axis.
• Familial glucocorticoid deficiency (FGD) results from isolated cortisol deficiency, with MC2R mutations causing ~25% of cases.
• MC2R accessory protein (MRAP) mutations account for ~20% of FGD, highlighting its role in MC2R function.

Purpose of the Study:

• To investigate the role of MRAP in adrenal physiology using mouse models.
• To compare the utility of Mc2r-knockout and Mrap-knockout mouse models in studying FGD.
• To elucidate the impact of MRAP deficiency on adrenal gland development and signaling pathways.

Main Methods:

• Generation and analysis of Mc2r-knockout and Mrap-knockout mouse models.
• Phenotypic characterization of adrenal glands in knockout mice.
• Assessment of WNT4/beta-catenin and sonic hedgehog (SHH) pathway signaling.

Main Results:

• Mc2r-knockout mice exhibited deficiencies in glucocorticoid, mineralocorticoid, and catecholamines.
• Mrap-knockout mice accurately mimicked the human FGD phenotype with isolated glucocorticoid deficiency.
• Mrap-knockout mice displayed adrenal dysmorphology, including thickened capsules, disrupted zonation, and altered WNT4/beta-catenin and SHH signaling.

Conclusions:

• MRAP is essential for MC2R expression and function, critical for adrenal gland development.
• Mrap-knockout mice provide a superior model for studying isolated glucocorticoid deficiency (FGD).
• ACTH and MRAP are crucial for regulating adrenal progenitor cells, cortex maintenance, and zonation.