Role of sonic hedgehog in adrenal development

The adrenal glands are organs which sit above the kidneys and act as ?factories? producing steroid hormones. Different regions or ?zones? of the glands produce different steroids, some of which control blood pressure and others stress and glucose regulation and thus the correct development of these zones and the regulation of their steroid output are essential for health. Understanding the processes leading to the formation of the different zones will potentially allow better management of adrenal disorders, which can be fatal. We have shown that a controller of embryonic development, a protein called sonic hedgehog (Shh), is produced in the outer zone of the gland where it is thought the stem cells are located. These are cells which can give rise to all the other cells in the organ and it is thought that the correct regulation of their growth is essential for normal development, with defects leading to disease, including cancer. Shh is a ?morphogen?, a secreted protein which acts upon other cells to affect their behaviour and development, and has been shown to affect stem cells in other tissues. We aim to define the relationship between the stem cells and those that produce and respond to Shh within the adrenal in rats and mice and demonstrate that by altering the activity of Shh we can cause changes in the appearance of the adrenal zones and the amounts of steroids that they produce. These studies will be a great advance as to date we have little insight into how these processes are controlled.

The adrenal cortex is composed of three zones, the zona glomerulosa (ZG), zona fasciculata (ZF) and zona reticularis (ZR), which have a defined steroid output with mineralocorticoid and glucocorticoid synthesis in the ZG and ZF/ZR respectively. Although the development of the adrenal cortex during rodent and primate embryogenesis has been documented, there is no known controller of its development and zonation. Identification of cells with stem cell properties in the subcapsular region has led to the theory that cells within the ZG differentiate to populate the ZF and ZR, migrating in a centripetal manner. We have shown that the cell fate regulator sonic hedgehog (Shh) is expressed exclusively in the ZG, and the expression of other components of the Shh pathway is largely restricted to this zone. Intriguingly, adrenal pathologies have been linked to defects in Shh signalling.
The adrenal cortex is a dynamic organ which responds to stress and other physiological conditions by remodeling, that is changing the relative sizes of the zones to meet the hormonal needs of the organism. We aim to exploit these properties in the rodent to investigate the role of Shh in the control of cell proliferation, differentiation and ultimately the steroid output of the gland. We will undertake an extensive investigation of the expression of Shh and pathway components in the rat adrenal cortex during embryogenesis and also in the adult gland under normal conditions and those designed to stimulate adrenal remodeling. We will also block Shh signaling using the inhibitor cyclopamine and study the effects upon adrenal morphology and steroid output. These experiments will determine the role of Shh in adrenal development, growth and function. The data from these experiments will be compared to those obtained from mice in which we can manipulate Shh expression by conditional knockout. By verifying these animals as appropriate model systems we will then be able to exploit these resources to study the lineage of the Shh expressing cells. Other mouse mutants in which we can manipulate the expression of other pathway components will become available and allow rapid future advancement of this study. These experiments will not only address the mechanisms regulating the control of adrenal development and maintenance but also allow us to compare the function of Shh in organ development and homeostasis, which has not been investigated in other systems.