The establishment of the hepatic architecture is a prerequisite for the development of a lobular pattern of gene expression

We have studied the expression patterns of ammonia-metabolising enzymes and serum proteins in intraspleni-cally transplanted embryonic rat hepatocytes by in situ hybridisation and immunohistochemical analysis. The enzymic phenotype of individually settled hepatocytes was compared with that of hepatocytes being organised into a three-dimensional hepatic structure. Our results demon-strate that development towards the terminally differenti-ated state with zonal differences in enzyme content requires the incorporation of hepatocytes into lobular structures. Outside such an architectural context, phenotypic matura-tion becomes arrested and hepatocytes linger in the pro-todifferentiated state. These features identify the foetal period as a crucial time for normal liver development and show that the establishment of the terminally differentiated hepatocellular phenotype, beginning with the differen-tiation of hepatocytes from the embryonic foregut, is realised via a multistep process.