Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene.
We previously demonstrated that expression of an albumin-urokinase-type plasminogen activator (Alb-uPA) fusion construct in transgenic mice resulted in elevated plasma uPA concentration, hypofibrinogenemia, and neonatal hemorrhaging. Two lines of Alb-uPA mice were established in which only one half of the transgenic pups died at birth; surprisingly, plasma uPA concentrations in survivors gradually returned to normal by 2 months of age. The basis for this phenomenon is DNA rearrangement within hepatocytes that affects the transgene tandem array and abolishes transgene expression. Transgene-deficient cells selectively proliferate relative to surrounding liver, and this process culminates in replacement of the entire liver by clonal hepatic nodules derived from transgene-deficient progenitor cells. In some cases as few as two nodules can reconstitute over 90% of liver mass, highlighting the remarkable regenerative capacity of individual liver cells.
Sandgren
E P
EP
Laboratory of Reproductive Physiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104.
Palmiter
R D
RD
Heckel
J L
JL
Daugherty
C C
CC
Brinster
R L
RL
Degen
J L
JL
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000648:ultrastructure; D002872:Chromosome Deletion; D004261:DNA Replication; D004792:Enzyme Precursors / Q000502:physiology; D015870:Gene Expression; D008099:Liver / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010960:Plasminogen Activators / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012709:Serum Albumin / Q000032:analysis / Q000235:genetics*; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000032:analysis / Q000235:genetics
D004792:Enzyme Precursors; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D012709:Serum Albumin; D000509:alpha-Fetoproteins; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator