Popis: |
Thioredoxin 1 (Trx1) regulates redox signaling through reduction of cysteine thiols in protein substrates. Impaired Trx1 function has been implicated in the pathogenesis of several neurodegenerative, pulmonary, immune, metabolic and cardiovascular diseases as well as cancer. However, understanding and identifying Trx1-dependent redox signaling pathways with physiological relevance has been difficult since genetic ablation of Trx1 is embryonic lethal. To circumvent this limitation, we generated a mouse with loxP sites flanking exons 2-5 of Trx1 for temporal and spatial regulation of Trx1 expression via cre recombinase. Mice expressing cre recombinase in the germline were used to fix one recombined Trx1 allele. Breeding these Trx1 heterozygote offspring did not yield any viable pups with homozygous recombined Trx1 alleles, recapitulating the embryonic lethal phenotype. For spatial control of Trx1 expression, floxed Trx1 mice were bred with a mouse expressing cre recombinase off the promoter of Nkx2.1 (Nkx2.1-Cre), which is expressed in thyroid, lung epithelium and cortex (including hypothalamus). Although viable, mice lacking Trx1 in Nkx2.1-positive tissues had impaired perinatal growth. At weaning, mice with Trx1-deficient Nkx2.1-positive tissues weighed nearly 45% less than wild-type controls at 3 weeks-old (10.04±1.19g v. 5.55±0.87g). Circulating levels of growth hormone were decreased by 68% in mice with Trx1-deficient Nkx2.1-positive tissues (2179±1422pg/mL v. 685.1±353.6pg/mL). Upon close examination, there were gross anatomic abnormalities in the hypothalamic and pituitary regions due to Trx1-deficiency. In summary, we found that Trx1 function is required for both embryonic and perinatal growth and ongoing studies are examining the growth signaling and anatomy of the hypothalamic-pituitary axis. |