Identification of genes regulating the differentiation of adrenocotical stem cells and their functional mechanisms

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Mammalian adrenal codex is composed of three zones, the zona glomerulosa (zG), zona fasciculata (zF), and zona reticularis (zR). Each zone has a different function, though cells in three zones are of the same origin, I.e. mesodermal origin. So far, stem cells and/or projenitor cells of the adrenal corex have not been identified, and molecular mechanisms of the differentiation, formation and maintenance of adrenal corex have remained obscure. We previously found a functionally undifferentiated cell zone (zU) between zG and zF in rats. Replicating cells in the cortex were abundant in and around zU, suggesting that zU contains stem cells which are capable to differentiate into zG or zF/zR cells. To develop in vitro model systems for analyzing the differentiation processes, we attempted to obtain adrenocodical cell lines at the undifferentiated stage similar to that of zU cells. Cell lines with such properties were established from a primary culture of adrenal glands from transgenic mice harboring a temperature sensitive mutant of SV40 large T antigen gene. Then, we tried to clone cDNAs encoding proteins which were expressed specifically in the undifferentiated cell lines with the aid of differential hybridization screening. Several cDNA clones were isolated. One of the cDNA clones was found to presumably encode a new extracellular matrix protein. Another cDNA encoded a new protein whose amino acid sequence did not have any known homologous sequence. Their mRNAs were detected in the regions from zG to zU and from zU to zF, respectively. The sites of their expression corresponded to the regions where cell proliferation and differentiation of the adrenocodical cells took place most actively.These results suggest that the newly discovered proteins expressing specifically in the undifferentiated cell lines have roles in the differentiation of adrenocortical cells and also in the formation of the adrenal cortex.