Origins of zonation: the adrenocortical model of tissue development and differentiation

1. Although much work has addressed the functional significance of mammalian adrenocortical zonation, less attention has been paid to its developmental origins and the factors that maintain it. Recent concepts of tissue differentiation hold that cells respond to local morphogenic stimuli that are generated in a paracrine manner. 2. In fact, the adrenal cortex represents an ideal mammalian in vivo model for such studies: few others exist. While several components may contribute to the establishment of a developmental polarity in the gland, including products of capsular and neural elements, compelling evidence now suggests that the tissue renin-angiotensin system (RAS) has a critical role. 3. We have examined the roles of these and other paracrine morphogens and growth factors and of specific transcription factors in adrenocortical cellular proliferation and development. From data obtained by using in situ hybridization to determine their cellular location, we propose a hierarchy of potential tissue modelling agents. These include morphogens, such as angiotensin II derived from the intra-adrenal RAS, growth factors (e.g. basic fibroblast growth factor), which can be considered to be the paracrine amplifiers of the morphogenic signal, and, finally, transcription factors, such as C-fos, that directly stimulate mitosis and other events of differentiation.