scholarly journals Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) Lysophosphatidic Acid Receptor Knockout Mice: Signaling Deficits without Obvious Phenotypic Abnormality Attributable to lpa2

2002 ◽  
Vol 22 (19) ◽  
pp. 6921-6929 ◽  
Author(s):  
James J. A. Contos ◽  
Isao Ishii ◽  
Nobuyuki Fukushima ◽  
Marcy A. Kingsbury ◽  
Xiaoqin Ye ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Lysophosphatidic Acid ◽  
Knockout Mice ◽  
Cell Types ◽  
Fiber Formation ◽  
Mouse Development ◽  
Double Knockout ◽  
Cellular Effects ◽  
Cyclase Activation ◽  
Craniofacial Dysmorphism

ABSTRACT Lysophosphatidic acid (LPA), a bioactive lipid produced by several cell types including postmitotic neurons and activated platelets, is thought to be involved in various biological processes, including brain development. Three cognate G protein-coupled receptors encoded by lpa1 /lp A1/Edg-2/Gpcr26, lpa2 /lp A2/Edg-4, and lpa3 /lp A3/Edg-7 mediate the cellular effects of LPA. We have previously shown that deletion of lpa1 in mice results in craniofacial dysmorphism, semilethality due to defective suckling behavior, and generation of a small fraction of pups with frontal hematoma. To further investigate the role of these receptors and LPA signaling in the organism, we deleted lpa2 in mice. Homozygous knockout (lpa2 (−/−)) mice were born at the expected frequency and displayed no obvious phenotypic abnormalities. Intercrosses allowed generation of lpa1 (−/−) lpa2 (−/−) double knockout mice, which displayed no additional phenotypic abnormalities relative to lpa1 (−/−) mice except for an increased incidence of perinatal frontal hematoma. Histological analyses of lpa1 (−/−) lpa2 (−/−) embryonic cerebral cortices did not reveal obvious differences in the proliferating cell population. However, many LPA-induced responses, including phospholipase C activation, Ca2+ mobilization, adenylyl cyclase activation, proliferation, JNK activation, Akt activation, and stress fiber formation, were absent or severely reduced in embryonic fibroblasts derived from lpa1 (−/−) lpa2 (−/−) mice. Except for adenylyl cyclase activation [which was nearly abolished in lpa1 (−/−) fibroblasts], these responses were only partially affected in lpa1 (−/−) and lpa2 (−/−) fibroblasts. Thus, although LPA2 is not essential for normal mouse development, it does act redundantly with LPA1 to mediate most LPA responses in fibroblasts.

scholarly journals Individual Somatic H1 Subtypes Are Dispensable for Mouse Development Even in Mice Lacking the H10Replacement Subtype

2001 ◽  
Vol 21 (23) ◽  
pp. 7933-7943 ◽  
Author(s):  
Yuhong Fan ◽  
Allen Sirotkin ◽  
Robert G. Russell ◽  
Julianna Ayala ◽  
Arthur I. Skoultchi
Keyword(s):  
Knockout Mice ◽  
Knockout Mouse ◽  
Embryonic Stem ◽  
Mouse Development ◽  
Double Knockout ◽  
Linker Histones ◽  
Deficient Mice ◽  
Mouse Lines

ABSTRACT H1 linker histones are involved in facilitating the folding of chromatin into a 30-nm fiber. Mice contain eight H1 subtypes that differ in amino acid sequence and expression during development. Previous work showed that mice lacking H10, the most divergent subtype, develop normally. Examination of chromatin in H10−/− mice showed that other H1s, especially H1c, H1d, and H1e, compensate for the loss of H10 to maintain a normal H1-to-nucleosome stoichiometry, even in tissues that normally contain abundant amounts of H10 (A. M. Sirotkin et al., Proc. Natl. Acad. Sci. USA 92:6434–6438, 1995). To further investigate the in vivo role of individual mammalian H1s in development, we generated mice lacking H1c, H1d, or H1e by homologous recombination in mouse embryonic stem cells. Mice lacking any one of these H1 subtypes grew and reproduced normally and did not exhibit any obvious phenotype. To determine whether one of these H1s, in particular, was responsible for the compensation present in H10−/− mice, each of the three H1 knockout mouse lines was bred with H10 knockout mice to generate H1c/H10, H1d/H10, or H1e/H10double-knockout mice. Each of these doubly H1-deficient mice also was fertile and exhibited no anatomic or histological abnormalities. Chromatin from the three double-knockout strains showed no significant change in the ratio of total H1 to nucleosomes. These results suggest that any individual H1 subtype is dispensable for mouse development and that loss of even two subtypes is tolerated if a normal H1-to-nucleosome stoichiometry is maintained. Multiple compound H1 knockouts will probably be needed to disrupt the compensation within this multigene family.

scholarly journals Rho Guanosine Triphosphatase Mediates the Selective Stabilization of Microtubules Induced by Lysophosphatidic Acid

1998 ◽  
Vol 141 (1) ◽  
pp. 175-185 ◽  
Author(s):  
Tiffani A. Cook ◽  
Takayuki Nagasaki ◽  
Gregg G. Gundersen
Keyword(s):  
Lysophosphatidic Acid ◽  
Leading Edge ◽  
Cell Types ◽  
Cell Polarization ◽  
Fiber Formation ◽  
Asymmetric Distribution ◽  
Actin Stress Fiber ◽  
Stable States ◽  
Selective Stabilization ◽  
Guanosine Triphosphatase

The asymmetric distribution of stable, posttranslationally modified microtubules (MTs) contributes to the polarization of many cell types, yet the factors controlling the formation of these MTs are not known. We have found that lysophosphatidic acid (LPA) is a major serum factor responsible for rapidly generating stable, detyrosinated (Glu) MTs in serum-starved 3T3 cells. Using C3 toxin and val14 rho we showed that rho was both necessary and sufficient for the induction of Glu MTs by LPA and serum. Unlike previously described factors that induce MT stability, rho induced the stabilization of only a subset of the MTs and, in wound-edge cells, these stable MTs were appropriately oriented toward the leading edge of the cell. LPA had little effect on individual parameters of MT dynamics, but did induce long states of pause in a subset of MTs near the edge of the cell. Rho stimulation of MT stability was independent of actin stress fiber formation. These results identify rho as a novel regulator of the MT cytoskeleton that selectively stabilizes MTs during cell polarization by acting as a switch between dynamic and stable states of MTs rather than as a modulator of MT assembly and disassembly.

3-Deazaadenosine Inhibits Vasa Vasorum Neovascularization in Aortas of ApoE-/-/LDL-/- Double Knockout Mice

2008 ◽  
Vol 180 (S 1) ◽  
Author(s):  
AC Langheinrich ◽  
D Sedding ◽  
M Kampschulte ◽  
J Wilhelm ◽  
W Haberbosch ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Vasa Vasorum ◽  
Double Knockout

scholarly journals Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia

2014 ◽  
Vol 306 (2) ◽  
pp. F188-F193 ◽  
Author(s):  
Timo Rieg ◽  
Takahiro Masuda ◽  
Maria Gerasimova ◽  
Eric Mayoux ◽  
Kenneth Platt ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Plasma Concentrations ◽  
Sglt2 Inhibitor ◽  
Double Knockout ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Sglt2 Inhibition ◽  
Renal Glucose Reabsorption ◽  
Glucose Excretion ◽  
Free Plasma

In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1−/−) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1−/− vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1−/− vs. WT after 24 h (−33 vs. −11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1−/−. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ∼10-fold and reduced FGR to 44 ± 3% in WT and to −1 ± 3% in Sglt1−/−. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50–60% of filtered glucose is excreted.

Adenylyl cyclase activation by halide anions other than fluoride

1974 ◽  
Vol 61 (2) ◽  
pp. 781-787 ◽  
Author(s):  
Martin I. Kalish ◽  
Marco A. Pineyro ◽  
Barry Cooper ◽  
Robert I. Gregerman
Keyword(s):  
Adenylyl Cyclase ◽  
Cyclase Activation ◽  
Halide Anions

P2.55 Mstn/Dysf double knockout mice gain muscle mass but no strength

2011 ◽  
Vol 21 (9-10) ◽  
pp. 676-677
Author(s):  
V. Schoewel ◽  
S. Adams ◽  
C. Herrmann ◽  
U. Zacharias ◽  
M. Boschmann ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Knockout Mice ◽  
Double Knockout
Sign in / Sign up

Export Citation Format

Share Document