Are Hox genes responsible for the phenotypic switching and zonation of the adult adrenal cortex?
SE Neville, S Baigent & PJ Lowry
Adrenal cortical cells are continuously renewed in order to sustain production of relevant zonal steroids. Cell proliferation occurs at the periphery of the cortex where cells subsequently displace centripetally, switching phenotypically as they migrate though the gland and finally undergoing apoptosis at the medullary boundary. However, it is not known which mechanisms cause the cells to differentiate as they cross the zonal boundaries. A candidate group of genes involved in embryonic development are the retinoic acid (RA) activated Hox genes.
Using PCR and in-situ hybridisation, we have shown that nine Hox B cluster genes are expressed in the adult rat adrenal gland. As in the developing embryo, the genes display both spatial and temporal colinear expression patterns with the 3' gene Hox B2 being expressed within the capsule, B4 in the glomerulosa and the 5' genes B5 and B9 in the fasciculata/reticularis.
Interestingly, we have found that the human adrenal H295 cell line (known to behave in a pluripotent adrenocortical manner) expresses Hox genes B2, B4 and B5. In order to determine if RA is responsible for the temporal pattern of Hox gene expression, these cells were treated with varying doses of RA over a 120 hour time period. Basal levels of aldosterone significantly increased in a dose dependent manner over the first 24 hours there-after levels returned to control values. These results could be explained by the fact that the cells are responding to the RA-induced upregulation of 3'-located Hox genes resulting in them behaving temporarily as aldosterone-producing zona glomerulosa cells.
These initial findings suggest that Hox genes may be involved in cellular differentiation and zonation in the adult adrenal cortex and that, as in the developing embryo, RA may be one of the factors responsible for the activation of these genes.