The liver shows maximal cellular growth during fetal development and following partial hepatectomy. As hepatocytes proliferate during development, they begin to express genes responsible for the hepatic phenotype. Unlike other proliferative states in which dedifferentiation occurs, in liver regeneration following partial hepatectomy, expression of these liver-restricted genes is maintained, and in some cases increases. Dr. Taub's laboratory has examined the temporal expression of more than 70 immediate-early, delayed-early and liver-specific genes during the temporal course of liver regeneration, and defined a boundary at approximately 72 hours posthepatectomy whereupon the gene expression in the regenerating liver returns toward normal. Similarly, the expression of this large number of these genes has been examined in the fetal liver from several days prenatal to four weeks postnatal when the major growth phase of the developing liver ceases. As in liver regeneration, many immediate- early and delayed-early genes such as PRL-1 and beta-actin are expressed at a high level throughout the temporal course of liver development, and correlate with the proliferative state. However, a subset of immediate- early genes that are liver-restricted including IGFBP-1, CL-6, and RL- 1/(glucose-6-phosphatase(G6Pase) are expressed primarily in the perinatal period. The level of fetal liver expression of these genes is as high as peak expression found in the regenerating liver. All of these genes demonstrate a basal level of expression in normal liver indicating that they may play a role in normal liver function. IGFBP-1 encodes a protein that is important in modulating the activities of IGFs, but its role in liver development and regeneration is not clear. G6Pase is important for hepatic glucose production, and CL-6 is a novel gene that encodes a hydrophobic protein of unknown function. The increased expression of these genes in proliferative states of the liver suggest that maintenance of differentiation is important for normal growth during liver regeneration and fetal hepatic development. Liver-specific transcription factors are likely to participate in the regulation of liver-restricted genes during hepatic development. It is not clear if liver-specific transcription factors participate in the induction of liver-restricted immediate-early genes during liver regeneration or if regeneration induced factors are entirely responsible for this induction. By understanding the regulation of expression and function of the liver-restricted proteins IGFBP-1 CL-6 and G6Pase in hepatic development and regeneration, we may gain insight into acquisition of the differentiated state during development and maintenance of the liver-specific phenotype during regeneration.
The aims of this project are to 1. Define the patterns of expression of liver- specific, growth-regulated genes during fetal liver development and assess the role of a specific hepatic transcription factor, C/EBPalpha, in their regulation. 2. Examine the basis for transcriptional activation of liver- specific genes IGFBP-l, CL-6, G6Pase during fetal liver development as compared to liver regeneration. 3. Determine the function of two liver- specific genes, IGFBP- l and CL-6, ascertain how they are contributing to the growth and differentiated state of the liver during development and following partial hepatectomy.
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