Prenylcysteine carboxylmethyltransferase is essential for the earliest stages of liver development in mice

Abstract

Background & Aims: Liver development, regeneration, and oncogenesis involve signaling events mediated by a number of proteins, such as ras and the related small guanosine triphosphatases. Many of these signaling proteins carry unique CAAX motifs, which are processed by prenylcysteine carboxylmethyltransferase (PCCMT), among several other enzymes. We investigated the function of Pccmt during mouse liver development to better understand the embryonic lethality of the null mutation. Methods: Generation of Pccmt-null mice by embryonic stem cell technology, molecular and histologic analysis of Pccmt-null embryos, and foregut endoderm cultures. Results: Pccmt-null embryos die in utero with severe anemia and extensive apoptosis at embryonic day 10.5. We show that deletion of Pccmt leads to a dramatic delay in albumin induction, an early and definitive marker for hepatocyte development. In tissue explant cultures supplemented with fibroblast growth factor (FGF), albumin induction remained impaired. We found that hepatocyte precursors in Pccmt-null embryos failed to invade the septum transversum, resulting in liver agenesis. Conclusions: PCCMT is essential for several stages of hepatic induction, consistent with its role in modifying proteins required to transduce signals, such as FGF, that have been shown to promote liver specification and early growth.