scholarly journals Growth hormone and fertility in oMt1a-oGH transgenic mice

Reproduction ◽  
2001 ◽  
pp. 537-544 ◽  
Author(s):  
AD Thomas ◽  
JD Murray ◽  
TR Famula ◽  
AM Oberbauer
Keyword(s):  
Growth Hormone ◽  
Transgenic Mice ◽  
High Growth ◽  
Plasma Corticosterone ◽  
Leptin Resistance ◽  
Wild Type ◽  
Embryonic Survival ◽  
Treatment Groups ◽  
Female Mice ◽  
Wild Type Female

Female mice carrying a regulatable growth hormone transgene (oMt1a-oGH) are subfertile when the transgene is actively expressed. This study was designed to characterize subfertility caused by increased concentrations of growth hormone. In particular, this study aimed to: (i) determine the effects of transgene activation and inactivation on mating, conception, maintenance of pregnancy, ovulation rate, litter characteristics and embryonic survival at day 17 of pregnancy, (ii) characterize oestrous cyclicity in transgenic versus wild-type female mice, and (iii) correlate corticosterone concentrations with transgene expression and reproductive performance. Transgenic and wild-type female mice were allocated randomly to one of four treatment groups at weaning: (i) transgenic female mice that always express the transgene, (ii) transgenic female mice that never express the transgene, (iii) transgenic female mice that express the transgene for up to 8 weeks of age and (iv) non-transgenic wild-type female mice receiving the transgene stimulus until 8 weeks of age. Activation followed by inactivation of the transgene resulted in an increased incidence of remating, resulting in an extended interval to establish pregnancy in comparison with all other treatment groups. Transgenic mice that always expressed the transgene and those that expressed the transgene for up to 8 weeks of age had lower pregnancy rates and higher ovulation rates compared with mice from other treatment groups. Both embryonic survival and the duration of the oestrous cycle did not differ among treatment groups. Active expression of the transgene resulted in an increase in the plasma concentration of corticosterone, which was associated with reduced fertility. These data indicate that the presence of a high growth hormone concentration impedes the establishment and maintenance of pregnancy. Increased plasma corticosterone concentrations may interfere with implantation as well as potentiate leptin resistance, which has been reported previously in studies with these mice.

scholarly journals An Authentic Murine Model of Fetal/Neonatal Alloimmune Thrombocytopenia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 97-97
Author(s):  
Huiying Zhi ◽  
Maria Therese Ahlen ◽  
Trude Rasmussen ◽  
Bjørn Skogen ◽  
Peter J. Newman
Keyword(s):  
Amino Acid ◽  
Transgenic Mice ◽  
Murine Model ◽  
Conflicts Of Interest ◽  
Severe Thrombocytopenia ◽  
Wild Type ◽  
Amino Acid Polymorphism ◽  
Female Mice ◽  
Wild Type Female ◽  
Alloimmune Thrombocytopenia

Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies directed against paternally-inherited antigens present on the surface of fetal platelets. The human platelet alloantigen, HPA-1a (also known as the PlA1 alloantigen), is the most frequently implicated HPA for causing FNAIT in Caucasians. A single Leu33Pro amino acid polymorphism residing within the ~50 amino acid plexin/semaphorin/integrin (PSI) domain near the N-terminus of the integrin β3 subunit (platelet membrane glycoprotein (GP)IIIa), is responsible for generating the HPA-1a and HPA-1b epitopes in human GPIIIa. Neither human polyclonal nor mouse monoclonal anti-HPA-1a antibodies, however, recognize murine GPIIIa due to amino acid differences both within and surrounding the HPA-1a alloepitope. As a result, there are currently no authentic mouse models of FNAIT capable of recapitulating the human alloimmune response to this clinically important platelet alloantigen. We have recently shown that humanizing residues 30, 32, 33, and 39 within the PSI domain, as well as amino acid 470 within the linearly distant but conformationally close Epidermal Growth Factor (EGF) 1 domain, of murine GPIIIa, is sufficient to re-create the epitope recognized by most maternal anti-HPA-1a alloantibodies. We therefore used CRISPR/Cas9 gene editing technology to generate transgenic mice whose platelets express human residues A30P32L33D39Q470 on a murine GPIIIa backbone - hereafter referred to as APLDQ mice. Intraperitoneal injection of an anti-HPA-1a mAb induced severe thrombocytopenia in these APLDQ, but not wild-type, mice. Furthermore, platelets from APLDQ mice, when introduced into wild-type mice, elicited a strong polyclonal immune response that was specific for, and importantly restricted to, the epitopes created by these humanized residues, demonstrating that the APLDQ humanized form of murine GPIIIa is immunogenic in mice. Wild-type female mice pre-immunized with APLDQ platelets, when bred with APLDQ male mice, gave birth to severely thrombocytopenic pups, many of whom exhibited an accompanying bleeding phenotype. Notably, administration of intravenous immunoglobulin G (IVIG) into pregnant female mice at days 10 and 17 lowered the concentration of anti-APLDQ alloantibodies in both the maternal and fetal circulation, and importantly normalized the platelet count in the pups. Taken together, these data establish a novel murine model of FNAIT that recapitulates many of the clinically important features of FNAIT. Availability of APLDQ humanized transgenic mice should pave the way for the pre-clinical development and testing of novel therapeutic and prophylactic modalities to treat or prevent FNAIT in humans. Disclosures No relevant conflicts of interest to declare.

Genetic and demographic effects of single wild-type immigrants on a mutant population of Tribolium castaneum

1986 ◽  
Vol 28 (6) ◽  
pp. 1003-1008 ◽  
Author(s):  
Michael A. Delgado ◽  
DuWayne C. Englert
Keyword(s):  
Tribolium Castaneum ◽  
Wild Type ◽  
Gene Frequencies ◽  
Treatment Groups ◽  
Female Immigrant ◽  
Rate Of Increase ◽  
Wild Type Male ◽  
Wild Type Female ◽  
In The Wild ◽  
Type Gene

The effects of single wild-type immigrants on populations of Tribolium castaneum initially homozygous for the antennapedia (ap) allele were examined in reference to gene frequencies and age structures. One population received a wild-type male, another received a wild-type female, and the control population received no wild-type immigrant. The rate of increase in the wild-type gene frequency was significantly higher in the female immigrant population. Rapid increase in heterozygosity for this population resulted in a higher average number of adults than for the other two treatment groups. No significant differences in the numbers of larvae and pupae were observed. Results indicated increased larval survivability to be the major factor in establishment of the wild-type gene and the sex of the immigrant in the rate of increase.Key words: Tribolium, population, selection, immigration, antennapedia.

Abstract 367: Exercising Exacerbates the Hypertrophic Response of Female Transgenic Mice Expressing Elevated Myocardial Na + /H + Exchanger Isoform 1

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fatima Mraiche ◽  
Larry Fliegel
Keyword(s):  
Transgenic Mice ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Wild Type ◽  
Cross Sectional ◽  
Hypertrophic Response ◽  
Female Mice ◽  
Gender Specific

Cardiac hypertrophy (CH) is heart growth in response to environmental demands, and a variety of hormonal, paracrine and autocrine stimuli. It is a means to reduce stress on the ventricular wall. The Na+/H+ exchanger isoform 1 (NHE1) has been implicated in the development and progression of CH. To better understand the involvement of NHE1, male and female transgenic mice that express cardiac specific active NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. NHE activity of adult ventricular cardiomyocytes and protein expression were elevated by approximately 2 and 3-fold in the N- and K-line mice vs. control. The K-line female mice assessed by echocardiography demonstrated significant global cardiac dysfunction. Left ventricular fractional cell shortening and ejection fraction were significantly decreased in the K-line mice (23.1 ± 3.8% and 45.2 ± 6.9% K-line vs. 36.5 ± 1.1% and 66.4 ± 1.5% control, respectively; p<0.05). The K-line female mice also exhibit myocardial remodeling. The heart weight to body weight ratio was significantly greater in the K-line mice (143 ± 10.0% of control; P<0.05). Cross sectional area (K-line 195.6 ± 16.4% of control; p<0.05) and interstitial fibrosis (K-line: 275.4 ± 11.6% of control; p<0.05) were also elevated. Increased expression of active NHE1 protein in male mice was also much more detrimental than expression of the wild type protein as was seen with the female transgenic mice. Therefore, the NHE1 induced hypertrophic effect was not gender dependent. However, NHE1 expression induced gender specific differences with exercise. Exercising exaggerated the HW/BW ratio in female mice expressing activated NHE1 compared to males. These results suggest that gender specific activation of NHE1 may be critical in promoting hypertrophy in females in comparison with males.

A liver specific gene that is expressed in growth hormone transgenic mice and in normal female mice as a function of age

2006 ◽  
Vol 16 (3) ◽  
pp. 145-156 ◽  
Author(s):  
Jean D.R. Tiong ◽  
Elahu Gosney ◽  
Juan Ding ◽  
Edward Chin ◽  
John J. Kopchick
Keyword(s):  
Growth Hormone ◽  
Transgenic Mice ◽  
Specific Gene ◽  
Normal Female ◽  
Female Mice

scholarly journals Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas

Oncogene ◽  
2005 ◽  
Vol 24 (21) ◽  
pp. 3427-3435 ◽  
Author(s):  
Monica Fedele ◽  
Francesca Pentimalli ◽  
Gustavo Baldassarre ◽  
Sabrina Battista ◽  
Andres JP Klein-Szanto ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Natural Killer Cell ◽  
Transgenic Mice ◽  
Natural Killer ◽  
Pituitary Adenomas ◽  
Killer Cell ◽  
Wild Type ◽  
Prolactin Cell ◽  
Type Form ◽  
Wild Type Form

scholarly journals Cardiac contractile function is enhanced in isolated ventricular myocytes from growth hormone transgenic mice

2002 ◽  
Vol 173 (2) ◽  
pp. 257-264 ◽  
Author(s):  
PB Colligan ◽  
HM Brown-Borg ◽  
J Duan ◽  
BH Ren ◽  
J Ren
Keyword(s):  
Growth Hormone ◽  
Transgenic Mice ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Removal Rate ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Cardiac Contractile Function ◽  
Over Expression ◽  
Time To Peak

Growth hormone (GH) plays a key role in cardiac growth and function. However, excessive levels of GH often result in cardiac dysfunction, which is the major cause of death in acromegalic patients. Transgenic mice with GH over-expression serve as useful models for acromegaly and exhibit impaired cardiac functions using echocardiography, similar to those of human acromegaly. However, the mechanism underscoring the impaired ventricular function has not been well defined. This study was designed to evaluate the cardiac excitation-contraction coupling in GH over-expressing transgenic mice at the single ventricular myocyte level. Myocytes were isolated from GH and age-matched wild-type mouse hearts. Mechanical properties were evaluated using an IonOptix MyoCam system. The contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS) and time-to-90% relengthening (TR(90)), and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca2+ properties were evaluated by fura-2. GH transgenic mice exhibited significantly increased body weights and enlarged heart and myocyte size. Myocytes from GH transgenic mice displayed significantly enhanced PS and+/-dL/dt associated with similar TPS and TR(90) compared with the wild-type littermates. Myocytes from GH transgenic mice displayed a similar resting intracellular Ca2+ level and Ca2+ removal rate but exhibited an elevated peak intracellular Ca2+ level compared with the wild-type group. Myocytes from both groups were equally responsive to increases in extracellular Ca2+ concentration and stimulating frequency. These results suggest that GH over-expression is associated with enhanced contractile function in isolated myocytes and that the impaired cardiac function observed in whole hearts may not be due to defects at the myocyte level.

scholarly journals Growth hormone (GH) receptors, binding proteins and IGF-I concentrations in the serum of transgenic mice expressing bovine GH agonist or antagonist

1998 ◽  
Vol 158 (1) ◽  
pp. 53-59 ◽  
Author(s):  
AI Sotelo ◽  
A Bartke ◽  
JJ Kopchick ◽  
D Turyn ◽  
Keyword(s):  
Growth Hormone ◽  
Transgenic Mice ◽  
Binding Proteins ◽  
Immunological Methods ◽  
Mouse Serum ◽  
Wild Type ◽  
High Concentration ◽  
Dwarf Phenotype ◽  
Igf I ◽  
Dwarf Mice

We have examined the regulation of hepatic growth hormone receptors (GH-R) and serum GH binding proteins (GHBP) in transgenic mice expressing an antagonist of bovine growth hormone (bGH), G119K-bGH, and consequently exhibiting a growth suppressed dwarf phenotype. Specific GHBP could be measured in transgenic dwarf mouse serum only by immunological methods (RIA), because these mice have a very high concentration of mutated bGH in circulation (> 1 microgram/ml) and, therefore, almost all GHBP is bound to G119K-bGH and cannot be quantitated in binding assays. The concentrations of GHBP were 0.6 +/- 0.4 nM and 1.7 +/- 0.4 nM for normal and dwarf mice respectively. The concentrations of free GHBP in normal mice and in transgenic mice expressing wild-type GH can be calculated using chromatographic techniques as the dissociation constant (Kd) and the ratio of bound 125I-GH to free 125I-GH in the serum ([GHBP]free = B/F.Kd). In agreement with the assumption that GHBP reflects GH-R status, liver uptake of injected labeled bGH was greatly reduced in transgenic dwarfs in comparison with normal mice or with transgenic mice expressing wild-type bGH (liver/blood ratio of 0.48 +/- 0.21, 2.7 +/- 0.2, and 1.3 +/- 0.3 respectively) indicating that the high concentration of the mutated bGH (G119K-bGH) prevents labeled bGH uptake, as was expected from the dwarf phenotype. 125I-bGH taken up by the liver of transgenic dwarf mice was found in a smaller molecular species than in normal mice, compatible with the presence of 1:1 [(GH-R):GH] complexes instead of the 2:1 [(GH-R)2:GH] or 2:2 [(GHBP)2:(GH)2] complexes found in normal mice. The concentration of IGF-I, the principal mediator of GH activity, in the G119K-bGH transgenic mice was correlated with the concentration of free GHBP. This allowed us to use free GHBP concentration as a marker of the effects of the active endogenous hormone (mGH) on liver receptors in the presence of different concentrations of the antagonist of GH. The levels of GHBP in serum, as well as the concentration of GH-R in liver microsomes from mice expressing the bGH antagonist, are up-regulated by the high concentration of G119K-bGH (85%), but significantly less so than that which could be expected for the same concentration of native GH (220-275%). This up-regulation suggests that the G119K-bGH antagonist is internalized and induces synthesis of the receptor and of the binding protein.

Human C-reactive protein impedes entry of leptin into the CNS and attenuates its physiological actions in the CNS

2016 ◽  
Vol 473 (9) ◽  
pp. 1215-1224 ◽  
Author(s):  
Jie Li ◽  
Dong Wei ◽  
Mark A. McCrory ◽  
Alexander J. Szalai ◽  
Gangyi Yang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Transgenic Mice ◽  
Negative Impact ◽  
Leptin Resistance ◽  
Related Protein ◽  
Wild Type ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Fluid Concentration ◽  
Agouti Related Protein

Defective central leptin signalling and impaired leptin entry into the CNS (central nervous system) represent two important aspects of leptin resistance in obesity. In the present study, we tested whether circulating human CRP (C-reactive protein) not only diminishes signalling of leptin within the CNS, but also impedes this adipokine's access to the CNS. Peripheral infusion of human CRP together with co-infused human leptin was associated with significantly decreased leptin content in the CSF of ob/ob mice. Furthermore, following peripheral infusion of human leptin, the CSF (cerebrospinal fluid) concentration of leptin in transgenic mice overexpressing human CRP was sharply lower than that achieved in similarly infused wild-type mice. Administration of LPS (lipopolysaccharide) to human CRP-transgenic mice dramatically elevated the concentrations of human CRP in the CSF. The i.c.v. (intracerebroventricular) delivery of human CRP into the lateral ventricles of ob/ob mice blocked the satiety and weight-reducing actions of human leptin, but not those of mouse leptin. I.c.v. injection of human CRP abolished hypothalamic signalling by human leptin, and ameliorated the effects of leptin on the expression of NPY (neuropeptide Y), AgRP (Agouti-related protein), POMC (pro-opiomelanocortin) and SOCS-3 (suppressor of cytokine signalling 3). Human CRP can impede the access of leptin to the CNS, and elevation of human CRP within the CNS can have a negative impact on the physiological actions of leptin.

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