Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice

10.1038/70598 ◽  
1999 ◽  
Vol 23 (4) ◽  
pp. 471-473 ◽  
Author(s):  
Kevin Manley ◽  
Thomas L. Shirley ◽  
Lorraine Flaherty ◽  
Anne Messer
Keyword(s):  
Transgenic Mice ◽  
Huntington Disease ◽  
Cag Repeat ◽  
Somatic Instability

scholarly journals Absence of Disease Phenotype and Intergenerational Stability of the Cag Repeat in Transgenic Mice Expressing the Human Huntington Disease Transcript

1996 ◽  
Vol 5 (2) ◽  
pp. 177-185 ◽  
Author(s):  
Y. P. Goldberg ◽  
M. A. Kalchman ◽  
M. Metzler ◽  
J. Nasir ◽  
J. Zeisler ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington Disease ◽  
Cag Repeat ◽  
Disease Phenotype

scholarly journals Propensity for somatic expansion increases over the course of life in Huntington disease

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Radhia Kacher ◽  
François-Xavier Lejeune ◽  
Sandrine Noël ◽  
Cécile Cazeneuve ◽  
Alexis Brice ◽  
...  
Keyword(s):  
Computational Model ◽  
Recent Work ◽  
Huntington Disease ◽  
Blood Cells ◽  
Cag Repeat ◽  
Post Mortem ◽  
Blood Samples ◽  
Somatic Instability ◽  
Mutation Carriers ◽  
Better Than

Recent work on Huntington disease (HD) suggests that somatic instability of CAG repeat tracts, which can expand into the hundreds in neurons, explains clinical outcomes better than the length of the inherited allele. Here, we measured somatic expansion in blood samples collected from the same 50 HD mutation carriers over a twenty-year period, along with post-mortem tissue from 15 adults and 7 fetal mutation carriers, to examine somatic expansions at different stages of life. Post-mortem brains, as previously reported, had the greatest expansions, but fetal cortex had virtually none. Somatic instability in blood increased with age, despite blood cells being short-lived compared to neurons, and was driven mostly by CAG repeat length, then by age at sampling and by interaction between these two variables. Expansion rates were higher in symptomatic subjects. These data lend support to a previously proposed computational model of somatic instability-driven disease.

REGULATION OF HUNTINGTIN PALITOYLATION AND ITS ROLE IN HUNTINGTON DISEASE

2008 ◽  
Vol 31 (4) ◽  
pp. 26
Author(s):  
Fiona BJ Young ◽  
Deborah Yu Deng ◽  
Roshni R Singaraja ◽  
Michael R Hayden
Keyword(s):  
Transgenic Mice ◽  
Huntington Disease ◽  
Health Research ◽  
Psychiatric Symptoms ◽  
Ex Vivo ◽  
Critical Role ◽  
Junior Trainee ◽  
Bac Transgenic Mice

Huntington Disease(HD) is an inherited and ultimately fatal neurodegenerative disease demonstrating both neurological and psychiatric symptoms. The protein huntingtin (htt) undergoes many post-translational modifications, such as phosphorylation, palmitoylation, and proteolysis. Palmitoylation, the process by which a 16-carbon fatty acid forms a thioester bond with cysteine residues, is a reversible modification known to influence protein trafficking and function. Huntingtin Interacting Protein 14 (HIP14) was identified as a major palmitoyl acyl transferase (PAT) that interacts robustly with wild-type htt, but has significantly reduced interaction with mutant polyglutamine expanded htt. HIP14is a major PAT for htt and palmitoylation of mutant htt by HIP14 is significantly reduced. Down regulation of HIP14 by siRNA in vitro results in increased cell death in neurons, whereas co-transfection with htt and HIP14 results in enhanced palmitoylation and reduction in number of inclusions. Our laboratory has developed a HIP14 knockout mouse (HIP14-/-), which demonstrates many HD-like features similar to those seen in the YAC128 transgenic mouse model of HD. Notably, these mice demonstrate a much earlier and more severe phenotype as compared to the YAC128 mice, suggesting a critical role for HIP14 in HD pathogenesis. The overarching goal of these studies is to explore the role of HIP14 and palmitoylation in the pathogenesis of HD using in vitro, in vivo, and ex vivo methods. A human Bacterial Artificial Chromosome (BAC) containing HIP14 was identified, prepared, and submitted for microinjection, and we have now generated HIP14-overexpressing transgenic mice. These mice are currently undergoing preliminary analyses, and a subset of founders will be selected to undergo further characterization. These human HIP14 BAC transgenic mice will represent the first mammalian model of PAT overexpression, and will significantly further our understanding of PAT activity in vivo. The YAC transgenic model for HD, developed previously in our laboratory, recapitulates many aspects of HD as seen in humans. After preliminary characterization of the human HIP14 BAC transgenic mice, these mice will be crossed to the YAC model of HD. We anticipate that overexpression of HIP14 in vivo will delay and/or ameliorate the features of HD observed in the YAC128 mouse, providing validation of this pathway as a potential therapeutic target for HD. F.B.J.Y. is supported by a Canadian Institutes of Health Research Walter and Jessie Boyd & Charles Scriver and Child & Family Research Institute –UBC MD/PhDStudentship Award. She also receives funding from the Michael Smith Foundation for Health Research as a Junior Trainee.

scholarly journals The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1;85(7):1983]

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 319-329 ◽  
Author(s):  
S Dziennis ◽  
RA Van Etten ◽  
HL Pahl ◽  
DL Morris ◽  
TL Rothstein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Transgene Expression ◽  
Heterologous Gene Expression ◽  
Myeloid Cells ◽  
Reporter Genes ◽  
Regulatory Elements ◽  
Specific Expression ◽  
High Level

Abstract CD11b is the alpha chain of the Mac-1 integrin and is preferentially expressed in myeloid cells (neutrophils, monocytes, and macrophages). We have previously shown that the CD11b promoter directs cell-type- specific expression in myeloid lines using transient transfection assays. To confirm that these promoter sequences contain the proper regulatory elements for correct myeloid expression of CD11b in vivo, we have used the -1.7-kb human CD11b promoter to direct reporter gene expression in transgenic mice. Stable founder lines were generated with two different reporter genes, a Thy 1.1 surface marker and the Escherichia coli lacZ (beta-galactosidase) gene. Analysis of founders generated with each reporter demonstrated that the CD11b promoter was capable of driving high levels of transgene expression in murine macrophages for the lifetime of the animals. Similar to the endogenous gene, transgene expression was preferentially found in mature monocytes, macrophages, and neutrophils and not in myeloid precursors. These experiments indicate that the -1.7 CD11b promoter contains the regulatory elements sufficient for high-level macrophage expression. This promoter should be useful for targeting heterologous gene expression to mature myeloid cells.

Interactions of insulin-like growth factor (IGF)-II and growth hormone in vivo: circulating levels of IGF-I and IGF-binding proteins in transgenic mice

1997 ◽  
pp. 701-708 ◽  
Author(s):  
A Blackburn ◽  
RA Dressendorfer ◽  
WF Blum ◽  
M Erhard ◽  
G Brem ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Standard Diet ◽  
Igf I ◽  
Igf Binding ◽  
B Mice

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

scholarly journals p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice

2013 ◽  
Vol 305 (7) ◽  
pp. H1010-H1019 ◽  
Author(s):  
Catherine L. Passariello ◽  
Marjorie Gayanilo ◽  
Michael D. Kritzer ◽  
Hrishikesh Thakur ◽  
Zoharit Cozacov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Cardiac Insufficiency ◽  
S6 Kinase ◽  
Transgenic Expression ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout ( RSK3−/−) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180; RSK3−/− mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.

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