scholarly journals Dissociation of Locomotor Activation and Suppression of Food Intake Induced by CRF in CRFR1-Deficient Mice

Endocrinology ◽  
2000 ◽  
Vol 141 (7) ◽  
pp. 2698-2702 ◽  
Author(s):  
Angelo Contarino ◽  
Françoise Dellu ◽  
George F. Koob ◽  
George W. Smith ◽  
Kuofen Lee ◽  
...  
Keyword(s):  
Corticotropin Releasing Factor ◽  
Mutant Mice ◽  
Receptor Subtypes ◽  
Null Mutant ◽  
Wild Type ◽  
Feeding Behaviors ◽  
The Central Nervous System ◽  
Locomotor Activation ◽  
Null Mutant Mice ◽  
Deficient Mice

ABSTRACT Corticotropin-releasing factor (CRF) systems are involved in locomotor and feeding behaviors. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the central nervous system. However, the role for each receptor in locomotor activity and feeding remains to be determined. Using CRFR1 null mutant mice, the present study examined the functional significance of this receptor in ambulation and feeding. CRF treatment of wild-type mice resulted in increased levels of locomotion whereas no change was observed in CRFR1-deficient mice as compared to vehicle-treated mutant mice. In contrast, CRF decreased food-water intake in both wild type and CRFR1-deficient mice equally. These results support an important role for CRFR1 in mediating CRF-induced locomotor activation, whereas other receptor subtypes, likely CRFR2, may mediate the appetite-suppressing effects of CRF-like peptides.

scholarly journals Neurons Expressing the Highest Levels of γ-Synuclein Are Unaffected by Targeted Inactivation of the Gene

2003 ◽  
Vol 23 (22) ◽  
pp. 8233-8245 ◽  
Author(s):  
Natalia Ninkina ◽  
Katerina Papachroni ◽  
Darren C. Robertson ◽  
Oliver Schmidt ◽  
Liz Delaney ◽  
...  
Keyword(s):  
Es Cells ◽  
Culture Conditions ◽  
Sensory Function ◽  
Mutant Mice ◽  
Null Mutant ◽  
Wild Type ◽  
Complete Inactivation ◽  
Null Mutant Mice

ABSTRACT Homologous recombination in ES cells was employed to generate mice with targeted deletion of the first three exons of the γ-synuclein gene. Complete inactivation of gene expression in null mutant mice was confirmed on the mRNA and protein levels. Null mutant mice are viable, are fertile, and do not display evident phenotypical abnormalities. The effects of γ-synuclein deficiency on motor and peripheral sensory neurons were studied by various methods in vivo and in vitro. These two types of neurons were selected because they both express high levels of γ-synuclein from the early stages of mouse embryonic development but later in the development they display different patterns of intracellular compartmentalization of the protein. We found no difference in the number of neurons between wild-type and null mutant animals in several brain stem motor nuclei, in lumbar dorsal root ganglia, and in the trigeminal ganglion. The survival of γ-synuclein-deficient trigeminal neurons in various culture conditions was not different from that of wild-type neurons. There was no difference in the numbers of myelinated and nonmyelinated fibers in the saphenous nerves of these animals, and sensory reflex thresholds were also intact in γ-synuclein null mutant mice. Nerve injury led to similar changes in sensory function in wild-type and mutant mice. Taken together, our data suggest that like α-synuclein, γ-synuclein is dispensable for the development and function of the nervous system.

Blockade of Glutamate Receptors and Barbiturate Anesthesia 

1999 ◽  
Vol 91 (5) ◽  
pp. 1329-1329 ◽  
Author(s):  
Daisy T. Joo ◽  
Zhigang Xiong ◽  
John F. MacDonald ◽  
Zhengping Jia ◽  
John Roder ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Sleep Time ◽  
Mutant Mice ◽  
Gamma Aminobutyric Acid ◽  
Null Mutant ◽  
Wild Type ◽  
Gaba A ◽  
Receptor Complexes ◽  
Null Mutant Mice

Background Barbiturates enhance gamma-aminobutyric acid type A (GABA(A)) receptor function and also inhibit the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. The relative contribution of these actions to the behavioral properties of barbiturates is not certain. Because AMPA receptor complexes that lack the GluR2 subunit are relatively insensitive to pentobarbital inhibition, GluR2 null mutant mice provide a novel tool to investigate the importance of AMPA receptor inhibition to the anesthetic effects of barbiturates. Methods GluR2 null allele (-/-), heterozygous (+/-), and wild-type (+/+) mice were injected with pentobarbital (30 and 35 mg/kg intraperitoneally). Sensitivity to anesthetics was assessed by measuring the latency to loss of righting reflex, sleep time, and the loss of corneal, pineal, and toe-pinch withdrawal reflexes. In addition, patch-clamp recordings of acutely dissociated CA1 hippocampal pyramidal neurons from (-/-) and (+/+) mice were undertaken to investigate the effects of barbiturates on kainate-activated AMPA receptors and GABA-activated GABA(A) receptors. Results Behavioral tests indicate that sensitivity to pentobarbital was increased in (-/-) mice. In contrast, AMPA receptors from (-/-) neurons were less sensitive to inhibition by pentobarbital (concentrations that produced 50% of the maximal inhibition [IC50], 301 vs. 51 microM), thiopental (IC50, 153 vs. 34 microM), and phenobarbital (IC50, 930 vs. 205 microM) compared with wild-type controls, respectively. In addition, the potency of kainate was greater in (-/-) neurons, whereas no differences were observed for the potentiation of GABA(A) receptors by pentobarbital. Conclusions The GluR2 null mutant mice were more sensitive to pentobarbital anesthesia despite a reduced sensitivity of GluR2-deficient AMPA receptors to barbiturate blockade. Our results indicate that the inhibition of AMPA receptors does not correlate with the anesthetic effects of barbiturates in this animal model. We postulate that the increase in the sensitivity to anesthetics results from a global suppression of excitatory neurotransmission in GluR2-deficient mice.

Role of components of the phagocytic NADPH oxidase in oxygen sensing

2002 ◽  
Vol 93 (4) ◽  
pp. 1357-1364 ◽  
Author(s):  
K. A. Sanders ◽  
K. M. Sundar ◽  
L. He ◽  
B. Dinger ◽  
S. Fidone ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Carotid Body ◽  
Minute Ventilation ◽  
Mutant Mice ◽  
Whole Body ◽  
Type I ◽  
Null Mutant ◽  
Wild Type ◽  
Null Mutant Mice

It has been hypothesized that O2sensing in type I cells of the carotid body and erythropoietin (EPO)-producing cells of the kidney involves protein components identical to the NADPH oxidase system responsible for the respiratory burst of phagocytes. In the present study, we evaluated O2sensing in mice with null mutant genotypes for two components of the phagocytic oxidase. Whole body plethysmography was used to study unanesthetized, unrestrained mice. When exposed to an acute hypoxic stimulus, gp91phox-null mutant and wild-type mice increased their minute ventilation by similar amounts. In contrast, p47phox-null mutant mice demonstrated increases in minute ventilation in response to hypoxia that exceeded that of their wild-type counterparts: 98.0 ± 18.0 vs. 20.0 ± 13.0% ( n = 11, P = 0.003). In vitro recordings of carotid sinus nerve (CSN) activity demonstrated that resting (basal) neural activity was marginally elevated in p47phox-null mutant mice. With hypoxic challenge, mean CSN discharge was 1.5-fold greater in p47phox-null mutant than in wild-type mice: 109.61 ± 13.29 vs. 72.54 ± 7.65 impulses/s ( n = 8 and 7, respectively, P = 0.026). Consequently, the hypoxia-evoked CSN discharge (stimulus-basal) was ∼58% larger in p47phox-null mutant mice. Quantities of EPO mRNA in kidney were similar in gp91phox- and p47phox-null mutant mice and their respective wild-type controls exposed to hypobaric hypoxia for 72 h. These findings confirm the previous observation that absence of the gp91phoxcomponent of the phagocytic NADPH oxidase does not alter the O2-sensing mechanism of the carotid body. However, absence of the p47phoxcomponent significantly potentiates ventilatory and chemoreceptor responses to hypoxia. O2sensing in EPO-producing cells of the kidney appears to be independent of the gp91phoxand p47phoxcomponents of the phagocytic NADPH oxidase.

scholarly journals Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(−/−) null mutant mice

1998 ◽  
Vol 330 (1) ◽  
pp. 149-153 ◽  
Author(s):  
R. Peter SINCLAIR ◽  
Nadia GORMAN ◽  
Tim DALTON ◽  
S. Heidi WALTON ◽  
J. William BEMENT ◽  
...  
Keyword(s):  
Mutant Mice ◽  
Null Mutant ◽  
Wild Type ◽  
Oxidation Activity ◽  
Aminolaevulinic Acid ◽  
Hepatic Microsomes ◽  
Absolute Requirement ◽  
Null Mutant Mice ◽  
Cytochrome P 450 ◽  
Mouse Lines

In the present study we have investigated the putative requirement for the cytochrome P-450 isoform CYP1A2 in murine uroporphyria, by comparing Cyp1a2(-/-) knockout mice with Cyp1a2(+/+) wild-type mice. Uroporphyria was produced by injecting animals with iron-dextran and giving the porphyrin precursor 5-aminolaevulinic acid in the drinking water. Some animals also received 3-methylcholanthrene (MC) to induce hepatic CYP1A2. In both protocols, uroporphyria was elicited by these treatments in the Cyp1a2(+/+) wild-type mice, but not in the null mutant mice. Uroporphyrinogen oxidation activity in hepatic microsomes from untreated Cyp1a2(+/+) mice was 2.5-fold higher than in Cyp1a2(-/-) mice. Treatment with MC increased hepatic CYP1A1 in both mouse lines and hepatic CYP1A2 only in the Cyp1a2(+/+) line, as determined by Western immunoblotting. MC increased hepatic ethoxy- and methoxy-resorufin O-dealkylase activities in both mouse lines, but increased uroporphyrinogen oxidation activity in the Cyp1a2(+/+) wild-type mice only. These results indicate the absolute requirement for hepatic CYP1A2 in causing experimental uroporphyria under the conditions used.

scholarly journals Development, Maintenance, and Function of the Adrenal Gland in Early Postnatal Proopiomelanocortin-Null Mutant Mice

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2555-2562 ◽  
Author(s):  
Jason Karpac ◽  
Dirk Ostwald ◽  
Stephanie Bui ◽  
Peggy Hunnewell ◽  
Malini Shankar ◽  
...  
Keyword(s):  
Adrenal Glands ◽  
Mutant Mice ◽  
Null Mutant ◽  
Wild Type ◽  
Normal Morphology ◽  
Adrenal Hormones ◽  
Adrenal Cells ◽  
Mouse Mutants ◽  
Null Mutant Mice ◽  
And Function

Abstract Adult mouse mutants homozygous for an engineered proopiomelanocortin (POMC)-null allele lack macroscopically distinct adrenal glands and circulating adrenal hormones. To understand the basis for this adrenal defect, we compared the development of adrenal primordia in POMC-null mice and littermate controls. POMC-null mutant mice are born with adrenal glands that are morphologically indistinguishable from those of their wild-type littermates. However, in mutants adrenal cells fail to proliferate postnatally and adrenals atrophy until they have disappeared macroscopically in the adult. While present, mutant adrenals are differentiated as evidenced by the presence of enzymes for the final steps in the synthesis of corticosterone, aldosterone, and catecholamines. However, in contrast to adrenals of wild-type littermates, adrenals of POMC-null mutants do not produce corticosterone, not even in response to acute stimulation with exogenous ACTH. They do produce aldosterone; however, it is produced at reduced levels correlating with adrenal size. Transplantation of POMC-null mutant adrenals to adrenalectomized wild-type littermates results in adrenals with normal morphology and production of both corticosterone and aldosterone. These findings demonstrate that POMC peptides are not required for prenatal adrenal development and that POMC peptides in addition to ACTH are required for postnatal proliferation and maintenance of adrenal structures capable of producing both glucocorticoids and mineralocorticoids.

scholarly journals Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2279-2288 ◽  
Author(s):  
Norio Suzuki ◽  
Osamu Ohneda ◽  
Satoru Takahashi ◽  
Masato Higuchi ◽  
Harumi Y. Mukai ◽  
...  
Keyword(s):  
Heart Development ◽  
Erythropoietin Receptor ◽  
Mutant Mice ◽  
Null Mutant ◽  
Wild Type ◽  
Erythroid Progenitors ◽  
Mouse Development ◽  
Specific Expression ◽  
Null Mutant Mice ◽  
Epor Expression

Erythropoietin (Epo) and its receptor (EpoR) are indispensable to erythropoiesis. Although roles besides angiogenesis, such as neuroprotection and heart development, have been reported for the Epo-EpoR system, the precise contribution of Epo-EpoR to these nonhematopoietic tissues requires clarification. Exploiting aGATA-1 minigene cassette with hematopoietic regulatory domains, we established 2 lines of transgene-rescued EpoR-null mutant mice expressing EpoR exclusively in the hematopoietic lineage. Surprisingly, despite the lack of EpoR expression in nonhematopoietic tissues, these mice develop normally and are fertile. As such, we could exploit them for analyzing the roles of the Epo-EpoR system in adult hematopoiesis and in nonhematopoietic tissues. These rescued lines showed a differential level of EpoR expression in erythroid cells; one expressed approximately 40%, and the other expressed 120% of the wild-type EpoR level. A colony formation assay showed that erythroid progenitors in the 2 mutant lines exhibit distinct sensitivity to Epo. The circulating Epo level was much higher in the transgenic line with a lower EpoR expression. In response to induced anemia, the plasma Epo concentrations increased in both lines. Notably, the timing of the peak of plasma Epo concentration was delayed in both lines of rescued mice compared with wild type, suggesting that, in wild-type mice, nonhematopoietic EpoR contributes to the regulation of plasma Epo concentration. We thus conclude that nonhematopoietic expression of EpoR is dispensable to normal mouse development and that the expression level of EpoR regulates erythropoiesis by controlling the sensitivity of erythroid progenitors to Epo.

scholarly journals Interleukin-6 Is an Essential Determinant of On-Time Parturition in the Mouse

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3996-4006 ◽  
Author(s):  
Sarah A. Robertson ◽  
Inge Christiaens ◽  
Camilla L. Dorian ◽  
Dean B. Zaragoza ◽  
Alison S. Care ◽  
...  
Keyword(s):  
Physiological Role ◽  
Prostaglandin Synthesis ◽  
Late Gestation ◽  
Mutant Mice ◽  
Prostaglandin E ◽  
Null Mutant ◽  
Wild Type ◽  
Expression Of Genes ◽  
Null Mutant Mice ◽  
Activation Cascade

IL-6 abundance in amniotic fluid and uterine tissues increases in late gestation or with infection-associated preterm labor. A role in regulation of labor onset is suggested by observations that IL-6 increases expression of genes controlling prostaglandin synthesis and signaling in isolated uterine cells, but whether IL-6 is essential for normal parturition is unknown. To evaluate the physiological role of IL-6 in parturition in mice, we investigated the effect of Il6 null mutation on the timing of parturition and expression of genes associated with uterine activation. Il6 null mutant mice delivered 24 h later than wild-type mice, although circulating progesterone fell similarly in both genotypes during the prepartal period. Il6 null mutant mice were also refractory to low doses of lipopolysaccharide sufficient to induce preterm delivery in wild-type mice. The characteristic late-gestation elevation in uterine expression of Oxtr mRNA encoding oxytocin receptor, and peripartal increases in Ptgfr and Ptgs2 mRNAs regulating prostaglandin synthesis and signaling were delayed by 24 h in Il6 null mutant mice. Conversely, Ptger4 mRNA encoding the prostaglandin E receptor-4 was abnormally elevated in late-gestation in Il6 null mutant mice. Administration of recombinant IL-6 from d 11.5 postcoitum until term restored the normal timing of delivery and normalized Ptger4 mRNA expression in late gestation. We conclude that IL-6 has a key role in controlling the progression of events culminating in parturition and that it acts downstream of luteolysis in the uterus to regulate genes involved in the prostaglandin-mediated uterine activation cascade.

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