Prenylcysteine carboxylmethyltransferase is essential for the earliest stages of liver development in mice.
OBJECTIVE
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.
Lin
Xi
X
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
Jung
Joonil
J
Kang
Dongcheul
D
Xu
Bisong
B
Zaret
Kenneth S
KS
Zoghbi
Huda
H
D000740:Anemia / Q000150:complications / Q000196:embryology; D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence / Q000502:physiology; D046508:Culture Techniques; D004622:Embryo, Mammalian / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000502:physiology; D005260:Female; D005313:Fetal Death / Q000209:etiology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D022781:Hepatocytes / Q000502:physiology; D008099:Liver / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D011496:Protein Methyltransferases / Q000235:genetics / Q000502:physiology*; D012709:Serum Albumin / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology
D012709:Serum Albumin; D005346:Fibroblast Growth Factors; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase