While co-localized with the mesodermal-like expressing cells, was preferentially co-expressed with and was significantly higher than had no observable effects on the adrenals, loss of was associated with remarkable phenotypes. molecules, and the activity of major paracrine effectors, including ligands of the sonic hedgehog and Wnt signaling pathways, are thought to play a major role. Particularly, the composition of the ECM, which exhibits substantial differences within each of the three histologically distinct concentric zones, has been shown to influence the differentiation status of adrenocortical cells. New data from other organ systems and different experimental Erlotinib mesylate paradigms strongly support the conclusion that the interactions of ECM components with cell-surface receptors and secreted factors are key determinants of cell fate. In this review, we summarize established and emerging data on the paracrine and autocrine regulatory loops that regulate the biology of the progenitor cell niche and propose a role for bioengineered ECM models in further elucidating this biology in the adrenal. (zG), the intermediate (zF), and the innermost (zR), which are responsible for the production of mineralocorticoids, glucocorticoids, and androgens, respectively (1). Although the morphological and physiological aspects of the adrenal cortex have been relatively Erlotinib mesylate well characterized, Erlotinib mesylate the regulatory mechanisms responsible for the establishment and maintenance of the three zones are not fully understood. In the last few years, sophisticated molecular techniques, such as lineage tracing, and genetically modified animals have significantly contributed to our understanding of the embryonic development and homeostasis of the adrenal cortex, illuminating key molecules and signaling pathways that are implicated in these processes (discussed below in Sections Progenitor Populations in the Adrenal Gland and Signaling Pathways and Adrenal Progenitors). Accordingly, the Wnt and the hedgehog pathways have emerged as major paracrine factors that regulate both organogenesis and homeostasis of the gland. Both are essential for the establishment and maintenance of an undifferentiated population of steroidogenic precursor cells in the periphery of the organ that continuously replenish the cortical cells of the three zones throughout life (discussed below in Sections Progenitor Populations in the Adrenal Gland Pten and Signaling Pathways and Adrenal Progenitors). While the effectors of the RAAS and the HPA axis [angiotensin 2 and adrenocorticotrophic hormone (ACTH), respectively] are considered primary endocrine mediators that promote activity of adrenocortical steroidogenic cells (2C4), recent data support that the (AGP). At the eighth week of human gestation (E10.5 in mice), the AGP divides into dorsomedial and ventrolateral portions, giving rise to the adrenal and gonadal is invaded by cells of the neural crest that coalesce centrally to form the adrenal medulla (12). Subsequently, the is surrounded by mesenchymal cells, which will ultimately form the adrenal capsule (13). At this point, compartmentalization of the adrenal cortex into two structurally distinct areas is evident: a central area, comprised of large polyhedric eosinophilic cells referred as the fetal zone, and a peripheral zone adjacent to the newly formed capsule comprised of small and basophilic cells, referred to as the definitive zone. While in mice this compartmentalization is subtle, in humans, the fetal zone predominates over the definitive zone, constituting up to 80% of the adrenal mass by the end of the gestation (9, 14). In addition, ultrastructural studies in humans have demonstrated the presence of a third zone, referred as the transitional or intermediate zone, which has intermediate morphologic characteristics between the fetal and the definitive zones (9). It has been suggested that after mid-gestation the transitional zone has the capacity to synthesize cortisol (9, 15). By the week 30 of human gestation, the definitive and the transitional zones have morphological features that resemble the adult zG and zF, respectively (16). In humans, the fetal cortex starts to regress by apoptosis soon after birth, completely disappearing Erlotinib mesylate after a few weeks (9). In mice, definitive evidence.