The specified hepatic endoderm (hepatoblasts), the bipotential progenitor for hepatocytes and bile duct epithelial cells, proliferates during the primordial stages of liver development. Despite extensive studies, the mechanism that regulates proliferation of bipotential hepatoblasts is not fully understood. Here we show that Id3, a negative regulator of helix-loop-helix transcription factors, is an important regulator of hepatoblast proliferation in the developing chick liver. Id3 was expressed in hepatoblasts at early developmental stages (stages 12-29) but not in hepatocytes at later developmental stages (stage 34 onwards). Depletion of Id3 in hepatoblasts by siRNA results in failure of cell proliferation, but is not associated with either cell death or failure of expression of Hhex and Fibrinogen, the earliest hepatoblast markers. These observations suggest that at early developmental stages, Id3 functions as a positive regulator of hepatoblast proliferation, independent of cell death or maintenance of the non-terminally differentiated state. Interestingly at later developmental stages, the expression pattern of Id3 is complementary to that of Albumin, a marker of mature hepatocytes. Overexpression of Id3 in liver explants delayed the initiation of Albumin expression. Taken together, our observations show that Id3 is not only a positive regulator of hepatoblast proliferation, but also an inhibitor of their differentiation into hepatocytes in the developing chick liver.
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