Charakterisierung der Selenoproteine Thioredoxinreduktase 1 und 2 anhand von Knock-out-Mausmodellen

Thioredoxin Reductases (TR) are ubiquitously expressed
Selenium-containing redox enzymes. By reducing different
intracellular substrates they protect cells from oxidative stress.
For mus musculus two members of the Thioredoxin Reductase gene
family have been characterized so far: TR1 and TR2. Whereas the
subcellular localization of TR1 is mainly cytoplasmatic, TR2 was
only found in mitochondria. The protein functions of TR1 and TR2
were investigated by examining genetically engineered mice. Here I
will present the establishment of a conditional TR1-knockout mouse
strain and the phenotypical characterization of TR1- and of
TR2-knockout mice, that have been established before. Both
knockouts, TR1 and TR2, showed to be embryonically lethal. TR1
deficient mouse embryos died at day 9.5, whereas TR2 deficient
mouse embryos died around day 13.0 of embryonic gestation. Total
deficiency of TR1 leads to strong developmental retardation and
malformations in organogenesis mostly affecting the turning of the
embryo, closure of neural tube, formation of head structures and
formation of somites. Thereby TR1 deficient embryos maximally reach
the developmental stage of normal E8.5 wildtype embryos. Neuronal
specific TR1 knockout mice show growth retardation and cerebellar
hypoplasia. Starting at the postnatal age of 10-14 days they loose
weight and show cerebellar ataxia and tremors. Recent results
indicate that mice die at the age of approximately 4 weeks. TR2
deficient embryos can already be recognized at embryonic day E11.5
due to a smaller embryo size and paler colour. Mice are retarded in
their status of organ differentiation and show malformations in
heart and liver development, possibly leading to fatal heart
failure or liver insufficiency. Besides that, TR2 deficient embryos
show decreased proliferation rates of hematopoetic progenitor cells
in the embryonic liver. Taken together these results indicate that
TR1 plays an important role in embryonic growth and organogenesis.
Besides, deficiency of TR2 is proposed to disturb primarily the
integrity of mitochondria and as a consequence affect processes
like cell proliferation and transdifferentiation – leading to
embryonic death. The functions of Thioredoxin Reductases 1 and 2 in
separate organ systems need to be further analyzed by using
conditional ablation strategies.