Identification of candidate growth-regulating genes that are overexpressedin late gestation fetal liver in the rat

We have shown previously that hepatocyte proliferation in the late gestatio n fetal rat is mediated by growth factor-independent mechanisms that are di stinct from the signaling pathways that promote proliferation of adult rat hepatocytes. In the present studies, we identified six candidate growth-reg ulating genes that are overexpressed in fetal rat liver (embryonic day 19, 2 days pre-term) relative to adult rat liver using suppressive subtractive hybridization. These included the following: Grb10, a growth factor recepto r binding protein; eps15, a growth factor receptor substrate; nuc2+, a reti noblastoma protein binding protein; cdc25B, a cell cycle tyrosine phosphata se; the peroxisome proliferator-activated receptor PPAR alpha; and a deoxyu ridine triphosphatase that functions as a PPARa binding partner. In every c ase, the ontogeny of the expression of these genes declined postnatally in a manner consistent with the transition from a fetal to an adult hepatocyte phenotype. None were found to be cell cycle-dependent, in that they did no t show expression that followed perinatal changes in hepatocyte cell cycle activity. Based on our identification of these genes and previous work char acterizing their role in growth regulation, we conclude that they may contr ibute to the mitogenic signaling phenotype of fetal rat hepatocytes. (C) 20 00 Elsevier Science B.V. All rights reserved.