What Do We Learn from Gene Deletion and Overexpression for Adrenal Function?

The adrenal gland affects many of the body’s physiological processes of endocrine, metabolic, and immunologic nature. It is crucial in the adaptation to stress as the central effector organ of both the stress systems of the body. Alterations in adrenal function may thus result in severe consequences for the integrity of the organism, and adrenal function is tightly regulated by a complex network of regulatory mechanisms. Endogenous and exogenous genetic alterations now allow a functional dissection and analysis of single components of both classical and newly discovered regulatory mechanisms for evaluating their physiological importance in an otherwise intact organism.

The combined analysis of animal models with genetic alterations of the HPA axis on distinct levels reveals that defects of central components of the HPA axis have much more subtle effects on the phenotype than do defects at the level of the adrenal gland, which are mostly lethal. Animal models with hypothalamic or pituitary dysfunction (CRH, CRH-R, or POMC) present an impaired stress response and several behavioral abnormalities, but otherwise no substantial alterations in phenotype. In contrast, impaired adrenal steroidogenesis (21-hydroxylase, StAR, SF-1) is perinatally lethal. Another interesting finding is that primary ablation of catecholamine synthesis in the adrenal medulla results in a high rate of perinatal lethality, whereas overexpression of these enzymes does not have any major effect on phenotype. While an intact catecholamine and glucocorticoid function seems crucial for prenatal and perinatal survival and development, deficits in these hormones in adult life are tolerated – at least under normal conditions.

These observations also indicate complex compensatory mechanisms in adrenal function regulation. Redundancy in these regulatory mechanisms is critical to maintaining the integrity of the organism and adapting to stress. Animal models also yield valuable insights and in vivo evidence for functional interactions between the two stress systems under both normal conditions and stress. The advent of genetically engineered animal models offers the opportunity to clarify the importance of additional and newly discovered factors that influence adrenal function. For example, the immune system and HPA axis interact closely. Gene deletions in lipid and steroid metabolism enzymes lead to lack or abundance of substrates, thus affecting hormone synthesis in the adrenal gland. Identifying transcriptional factors that direct the development of the pituitary and the adrenal gives valuable insights into pituitary and adrenal development and function mechanisms. Genetic defects of these transcription factors (LHX3, PROP1, and DAX1) affect adrenal function in animals and in humans.

Animal models may present a valuable tool in developing and evaluating new interventional strategies in the therapy of genetically defined diseases as has been shown for 21-hydroxylase-deficient mice that have been at least transiently treated with gene therapy strategies.