STEROIDOGENIC ENZYME P450C17 IS EXPRESSED IN THE EMBRYONIC CENTRAL-NERVOUS-SYSTEM

Neurosteroids are steroids that are synthesized de novo in the brain a nd include some classical (adrenal and gonadal steroids) and some uniq ue brain-specific steroids. Neurosteroids are thought to mediate their action through ion gated channel receptors such as gamma-aminobutyric acid, and N-methyl-D-aspartate rather than through classical nuclear steroid hormone receptors. Some enzymes involved in neurosteroidogenes is have been identified as those found in steroidogenic tissues, and s ome may be unique to the brain. We previously demonstrated that the me ssenger RNAs (mRNA) for the cholesterol side-chain cleavage enzyme, cy tochrome P450scc, and one form of 11 beta-hydroxylase, cytochrome P450 c11 beta, are regionally expressed in the adult rat brain. However, cy tochrome P450c17, which has 17-hydroxylase and 17,20-lyase activity an d is thought to be required for the synthesis of dehydroepiandrosteron e, was not detected in any region of the rat brain, even though dehydr oepiandrosterone is one of the most abundant neuroactive steroids. We now demonstrate that P450c17 is expressed in the nervous system of the developing rodent embryo. By ribonuclease protection assays, P450c17 mRNA was found in the trunk but not in the head of rat embryos but rev erse transcriptase-polymerase chain reaction analysis showed expressio n of P450c17 mRNA in the head of E15.5 to E19.5 rat embryos. Immunocyt ochemically detectable P450c17 protein was expressed in the nervous sy stem as early as embryonic day E10.5 in the mouse, mainly in tissue de rived from the neural crest. Neuronal cell bodies as well as fibers st aining for P450c17 were observed in the central and peripheral nervous systems. The sites of P450c17 expression in the peripheral nervous sy stem suggest it may be involved in a wide variety of sensory-motor fun ctions. In the central nervous system, cell bodies expressing P450c17 are found in the hind brain, in mesencephalic nuclei, and in a region in the location of the locus coeruleus, but in cells distinct from tho se expressing the dopamine-beta-hydroxylase. Furthermore, its particul ar location and temporal expression in axons reaching the cortical are as suggest it is a marker for the axonal growth in this region, and th at its neurosteroid product may be a signal for targeting cortical axo ns during embryogenesis.