Arginine Decarboxylase and Agmatinase: An Alternative Pathway for De Novo Biosynthesis of Polyamines for Development of Mammalian Conceptuses1

Wang, Xiaoqiu; Ying, Wei; Dunlap, Kathrin A.; Lin, Gang; Satterfield, M. Carey; Burghardt, Robert C.; Wu, Guoyao

doi:10.1095/biolreprod.113.114637

Cited by 86 publications

(97 citation statements)

References 50 publications

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“…The MAO-Control had the sequence CCTCTTACCTCAGTTACAATTTATA. All morpholinos were synthesized with a 3 0 -lissamine modification to detect and confirm uptake of each MAO by the trophectoderm, while confirming absence of uptake by uterine epithelia (see Wang et al 2014).…”

Section: Studymentioning

confidence: 99%

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

Ruiz-Gonzalez¹,

Minten²,

Wang³

et al. 2015

Reproduction

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Toll-like receptors (TLRs) belong to the innate immune system and regulate inflammatory events that affect mammalian reproduction.In Study 1, we demonstrated that abundance of ovine TLR1-TLR9 mRNAs in the uterus differs due to reproductive status (TLR2, TLR3, TLR7, and TLR8) and the day of the estrous cycle and pregnancy (TLR1-TLR3, TLR5-TLR7, and TLR9). Expression of TLR7 and TLR8 proteins was localized primarily to uterine epithelia and stroma and regulated in a temporal manner. In Study 2, we determined that ovine conceptuses express TLR7 and TLR8 on all days studied and that expression of the envelope protein of ovine endogenous retrovirus (enJSRV-Env) declined in conceptus trophectoderm from Day 13 to Day 16 of pregnancy. In Study 3, loss-of-function experiments were conducted in vivo using morpholino antisense oligonucleotides (MAOs) injected into the uterine lumen to block synthesis of TLR7 and TLR8 proteins, individually and jointly. Conceptuses were recovered on Day 16 to assess their morphology. MAO-treated conceptuses were developmentally retarded, produced less interferon tau (IFNT), and had fewer binucleate cells (BNCs) compared with MAO-Controls. Moreover, expression of enJSRV-Env mRNA in MAO-TLR7 conceptuses was greater than that for MAO-Control and MAO-TLR8 conceptuses, but similar to MAO-TLR7/TLR8 conceptuses. Results of this study indicated differences in TLR1-TLR9 expression due to reproductive status and the day of the estrous cycle and pregnancy. TLR7 and TLR8 also influence development, enJSRV-Env abundance, secretion of IFNT, and formation of BNCs by conceptuses. These findings corroborate our hypothesis that TLR7 and TLR8 mediate pathways whereby enJSRV-Env regulates key peri-implantation events in conceptus development and differentiated functions of trophectoderm cells.

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Section: Studymentioning

confidence: 99%

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

Ruiz-Gonzalez¹,

Minten²,

Wang³

et al. 2015

Reproduction

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“…The amount of interferon-tau (IFNT) in the uterine flush was quantified using a radioimmunoassay developed at Colorado State University, using recombinant ovine IFNT (roIFNT) protein and anti-roIFNT polyclonal antibody (1:60 000 dilutin) as reported previously [7,11,31]. This radioimmunoassay was optimized for detection of IFNT in uterine flushings at a sensitivity of 0.1 ng/ml and a range of detection of 0.1-13 ng/ml.…”

Section: Radioimmunoassay Of Interferon-taumentioning

confidence: 99%

“…Concentrations of amino acids, agmatine, and polyamines were determined in uterine flushes and conceptuses as previously described [7,11,[34][35][36]. Briefly, uterine flushes (100 ll) or conceptuses (;20 mg) were acidified with 200 ll of 1.5 M HClO 4 and neutralized with 100 ll of 2 M K 2 CO 3 .…”

Section: Analyses Of Amino Acids Polyamines and Agmatinementioning

confidence: 99%

“…Deficiencies in the composition of uterine histotroph prevent or stunt development of conceptuses [4,5]. Of particular interest is the physiological amount of arginine (a nutritionally essential amino acid) that is critical for conceptus growth and development [6,7], including synthesis of nitric oxide (NO) via NO synthase (NOS) and polyamines (putrescine, spermidine, spermine) via ornithine decarboxylase (ODC1) [8][9][10] and, as we recently discovered, the arginine decarboxylase (ADC) and the agmatinase (AGMAT) pathway for mammalian synthesis of polyamine [11]. NO is a major regulator of angiogenesis and uteroplacenta-fetus blood flow that affects delivery of nutrients and oxygen from mother to fetus [12][13][14][15], whereas polyamines have key roles for DNA [16][17][18] and protein synthesis, scavenging reactive oxygen species [19], and stimulating proliferation [20][21][22] and differentiation of cells [21,23].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous studies of pregnant ewes during the periimplantation period of pregnancy revealed that 1) arginine increases substantially in both the ovine uterine lumen and conceptuses [6,11]; 2) physiological levels of arginine activate the mechanistic target of rapamycin complex 1 (MTORC1) cell signaling pathway in primary ovine trophectoderm (oTr) cells in vitro, thereby enhancing proliferation, attachment, and elongation of conceptus trophectoderm (Tr) for implantation [20,24,25]; 3) expression of transporters for arginine in uterine epithelia (SLC7A1 and SLC7A2) and conceptuses (SLC7A1) increases [26]; 4) ODC1 as well as ADC and AGMAT are key enzymes for synthesis of polyamines in conceptus Tr [11]; 5) NOS3 (endothelial NOS) rather than NOS1 (neuronal NOS) or NOS2 (inducible NOS) is abundant in Tr and endoderm of peri-implantation ovine conceptuses [27]; 6) in vivo translational knockdown of SLC7A1 mRNA, the major transporter of arginine in conceptuses, retards embryonic development [7]; and 7) in vivo translational knockdown of ODC1 mRNA in conceptuses results in variable phenotypes based on their ability to activate the novel and alternative ADC/AGMAT pathway for synthesis of polyamines, as polyamine-deficient conceptuses fail to elongate [11]. These results revealed the importance of arginine during the peri-implantation period of pregnancy in sheep.…”

Section: Introductionmentioning

confidence: 99%

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Functional Role of Arginine During the Peri-implantation Period of Pregnancy. II. Consequences of Loss of Function of Nitric Oxide Synthase NOS3 mRNA in Ovine Conceptus Trophectoderm1

Wang

Frank

et al. 2014

Biology of Reproduction

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Nitric oxide (NO) is a gaseous molecule that regulates angiogenesis and vasodilation via activation of the cGMP pathway. However, functional roles of NO during embryonic development from spherical blastocysts to elongated filamentous conceptuses (embryo and extraembryonic membrane) during the peri-implantation period of pregnancy have not been elucidated in vivo. In order to assess roles of NO production in survival and development of the ovine conceptus, we conducted an in vivo morpholino antisense oligonucleotide (MAO)-mediated knockdown trial of nitric oxide synthase-3 (NOS3) mRNA, the major isoform of NO synthase, in ovine conceptus trophectoderm (Tr). Translational knockdown of NOS3 mRNA results in small, thin, and underdeveloped conceptuses, but normal production of interferon-tau, the pregnancy recognition signal in sheep. MAO-NOS3 knockdown in conceptuses decreased the abundance of NOS3 (72%, P , 0.05) and the arginine transporter SLC7A1 proteins in conceptus Tr. Furthermore, the amounts of ornithine and polyamines were less (P , 0.01) in uterine fluid, whereas the amounts of arginine (58%, P , 0.01), citrulline (68%, P , 0.05), ornithine (68%, P , 0.001), glutamine (78%, P , 0.001), glutamate (68%, P , 0.05), and polyamines (P , 0.01) were less in conceptuses, which likely accounts for the failure of MAO-NOS3 conceptuses to develop normally. For MAO-NOS3 conceptuses, there were no compensatory increases in the expression levels of either nitric oxide synthase-1 (NOS1) or nitric oxide synthase-2 (NOS2) or in expression of enzymes for synthesis of polyamines (ornithine decarboxylase, arginine decarboxylase, agmatinase) from arginine or ornithine with which to rescue development of MAO-NOS3 conceptuses. Thus, the adverse effect of MAO-NOS3 to reduce NO generation and the transport of arginine and ornithine into conceptuses is central to an explanation for failure of normal development of MAO-NOS3, compared to control conceptuses. The study, for the first time, created an NO-deficient mammalian conceptus model in vivo and provided new insights into the orchestrated events of conceptus development during the peri-implantation period of pregnancy. Our data suggest that NOS3 is the key enzyme for NO production by conceptus Tr and that this protein also regulates the availability of arginine in conceptus tissues for synthesis of polyamines that are essential for conceptus survival and development.development, morpholino, nitric oxide, nitric oxide synthase

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Functional amino acids in the development of the pig placenta

Bazer

Johnson

et al. 2017

Molecular Reproduction Devel

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The mammalian placenta is essential for supplying nutrients (e.g., amino acids and water) and oxygen from the mother to fetus and for removing fetal metabolites (e.g., ammonia and CO 2 ) from fetus to mother. Thus, placental growth and development are determinants of fetal survival, growth, and development. Indeed, low birth weight is closely associated with reduced placental growth. Providing gestating gilts or sows with dietary supplementation of arginine and glutamine, increases placental growth (including vascular growth), improves embryonic/fetal growth and survival, and reduces the large variation in birth weight among litters. These two amino acids serve as building blocks for tissue protein as well as substrates for the production of polyamines and nitric oxide, which stimulate DNA and protein synthesis and angiogenesis and vascular growth in the placenta. These recent findings not only greatly advance the field of mammalian amino acid metabolism and nutrition, but also provide practical, mechanism-based methods to enhance reproductive efficiency in swine. These results may also help improve embryonic/fetal survival and growth in other livestock species (e.g., sheep and cattle) and in humans. K E Y W O R D Sarginine, fetus, glutamine, growth, nutrition, reproduction Dietary supplementation . . . during late gestation, not only improves fetal survival and growth but also decreases variation in birth weights of live born piglets.

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Arginine Decarboxylase and Agmatinase: An Alternative Pathway for De Novo Biosynthesis of Polyamines for Development of Mammalian Conceptuses1

Cited by 86 publications

References 50 publications

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

Functional Role of Arginine During the Peri-implantation Period of Pregnancy. II. Consequences of Loss of Function of Nitric Oxide Synthase NOS3 mRNA in Ovine Conceptus Trophectoderm1

Functional amino acids in the development of the pig placenta

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