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Thioredoxin-1 is Required for Embryonic and Perinatal Growth Signaling
DOI: 10.1016/j.freeradbiomed.2017.10.283
Signal Transduction / Redox Signaling
271
270 Thioredoxin-1 is Required for Embryonic and Perinatal Growth Signaling Erika Hernandez1, Alexandra Fairchild1, and Peter Vitiello1 Sanford Research, USA
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, 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 wildtype 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.
182
Mitochondrial Biogenesis and Bioenergetics Takaaki Akaike1, Akira Nishimura1, Tomoaki Ida1, Tetsuro
Thioredoxin 1 (Trx1) regulates redox signaling through
understanding
Synthetases: Cycteine Hydropersulfide Production and Regulation of
Cassandra Aegerter1, Benjamin Forred1, Xaviera Thomas1,
1
Moonlighting Functions of Cysteinyl-tRNA
Matsunaga1, Masanobu Morita1, and Hozumi Motohashi2 1
Tohoku University Graduate School of Medicine, Japan
2
IDAC, Tohoku University, Japan
Hydrogen sulfide and reactive persulfide species such as cysteine hydropersulfide (CysSSH) are reportedly formed endogenously in prokaryotic and eukaryotic cells and in mammals in vivo. The chemical properties and abundance of these species suggest a pivotal role for reactive persulfides (i.e., various compounds containing -SSH) in different cellular regulatory processes.
We proposed that
CysSSH and related reactive sulfur species can behave as potent antioxidants and cellular protectants and may function as redox signaling intermediates.
Extensive
persulfide formation is now apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is thus far believed to result from post-translational modifications involving hydrogen sulfide-related chemistry.
Here, we
discovered moonlighting (dual) functions of cysteinyl-tRNA synthetases
(CARSs), serve
as
the
principal cysteine
persulfide synthase (CPERS) in vivo. Targeted disruption of a gene encoding mitochondrial CARS (CARS2) in mice and human cells revealed that persulfides derived from CARS2 are critically involved in the mitochondrial biogenesis and energy metabolism, i.e., bioenergetics, which is known for a long time as sulfur respiration in anaerobic bacteria. Further investigating CARS-dependent persulfide production will clarify aberrant redox signaling that we may call as sulfur stress and a unique energy metabolism in mammals. References: Nishida, M., et al., Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Nat. Chem. Biol. 8, 714-724 (2012).
SfRBM 2017
Signal Transduction / Redox Signaling
271
270 Thioredoxin-1 is Required for Embryonic and Perinatal Growth Signaling Erika Hernandez1, Alexandra Fairchild1, and Peter Vitiello1 Sanford Research, USA
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, 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 wildtype 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.
182
Mitochondrial Biogenesis and Bioenergetics Takaaki Akaike1, Akira Nishimura1, Tomoaki Ida1, Tetsuro
Thioredoxin 1 (Trx1) regulates redox signaling through
understanding
Synthetases: Cycteine Hydropersulfide Production and Regulation of
Cassandra Aegerter1, Benjamin Forred1, Xaviera Thomas1,
1
Moonlighting Functions of Cysteinyl-tRNA
Matsunaga1, Masanobu Morita1, and Hozumi Motohashi2 1
Tohoku University Graduate School of Medicine, Japan
2
IDAC, Tohoku University, Japan
Hydrogen sulfide and reactive persulfide species such as cysteine hydropersulfide (CysSSH) are reportedly formed endogenously in prokaryotic and eukaryotic cells and in mammals in vivo. The chemical properties and abundance of these species suggest a pivotal role for reactive persulfides (i.e., various compounds containing -SSH) in different cellular regulatory processes.
We proposed that
CysSSH and related reactive sulfur species can behave as potent antioxidants and cellular protectants and may function as redox signaling intermediates.
Extensive
persulfide formation is now apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is thus far believed to result from post-translational modifications involving hydrogen sulfide-related chemistry.
Here, we
discovered moonlighting (dual) functions of cysteinyl-tRNA synthetases
(CARSs), serve
as
the
principal cysteine
persulfide synthase (CPERS) in vivo. Targeted disruption of a gene encoding mitochondrial CARS (CARS2) in mice and human cells revealed that persulfides derived from CARS2 are critically involved in the mitochondrial biogenesis and energy metabolism, i.e., bioenergetics, which is known for a long time as sulfur respiration in anaerobic bacteria. Further investigating CARS-dependent persulfide production will clarify aberrant redox signaling that we may call as sulfur stress and a unique energy metabolism in mammals. References: Nishida, M., et al., Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Nat. Chem. Biol. 8, 714-724 (2012).
SfRBM 2017