Summary
Prothrombin has diverse biological functions in addition to its well established role
in blood coagulation. In order to study these functions in more detail mouse model
systems are needed. Since deficiency of prothrombin in mice results in partial embryonic
lethality and neonatal death, alternative approaches are required to study the biology
of prothrombin in the adult mouse. The liver is the major site of synthesis of prothrombin
and therefore liver-specific promoters were used to express prothrombin in transgenic
mice. Mice generated from crosses with these transgenic mice and mice hemizygous for
the knock-out allele were used to test whether liver-specific expression is sufficient
to correct the phenotype of null mice and whether liver-specific expression is sufficient
for the development and survival of mice to adulthood. The mouse albumin promoter/enhancer
was used initially for transgene expression without success in obtaining transgene
positive, endogenous prothrombin null mice. Two lines of transgene positive, endogenous
prothrombin deficient mice were obtained using the mouse transthyretin (TTR) promoter/enhancer
driving expression of a human prothrombin cDNA. One line was able to rescue both the
embryonic and the neonatal lethality while the other line was only able to correct
the embryonic lethality. Expression of prothrombin was restricted to the liver and
stomach in one line and to the liver, pancreas, stomach and kidney in the other line
of mice. Thrombin activity for one line was determined to be at 5-10% of wildtype
levels. These mice developed normally and did not have spontaneous bleeding events
unless traumatized. Therefore, transgenic expression of human prothrombin is sufficient
for the rescue of the lethality found for prothrombin deficiency in mice.
Keywords
Prothrombin - thrombin - transgenic mice - transthyretin promoter
