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St. Louis, MO, United States

Liu Z.,SAGE Labs | Liu Z.,Washington University in St. Louis | Brunskill E.,Childrens Hospital Medical Center | Boyle S.,Washington University in St. Louis | And 9 more authors.
Development (Cambridge) | Year: 2015

We have previously described the creation and analysis of a Notch1 activity-trap mouse line, Notch1 intramembrane proteolysis-Cre6MT or N1IP::CreLO, that marked cells experiencing relatively high levels of Notch1 activation. Here, we report and characterize a second line with improved sensitivity (N1IP::CreHI) to mark cells experiencing lower levels of Notch1 activation. This improvement was achieved by increasing transcript stability and by restoring the native carboxy terminus of Cre, resulting in a five- to tenfold increase in Cre activity. The magnitude of this effect probably impacts Cre activity in strains with carboxy-terminal Ert2 fusion. These two trap lines and the related line N1IP::CreERT2 form a complementary mapping tool kit to identify changes in Notch1 activation patterns in vivo as the consequence of genetic or pharmaceutical intervention, and illustrate the variation in Notch1 signal strength from one tissue to the next and across developmental time. © 2015. Published by The Company of Biologists Ltd. Source


Ji D.,SAGE Labs | Zhao G.,SAGE Labs | Songstad A.,SAGE Labs | Cui X.,SAGE Labs | Weinstein E.J.,SAGE Labs
Transgenic Research | Year: 2015

The rabbit is a preferred model system for diverse areas of human disease research, such as hypertension and atherosclerosis, for its close resemblance to human physiology. Its larger size than that of rodents allows for more convenient physiological and surgical manipulations as well as imaging. The rapid development of nuclease technologies enables the rabbit genome to be engineered as readily as that of rats and mice, offering rabbit models a chance to make their due impact on medical research. Here, we report the efficient creation of an APOE knockout rabbit by using zinc finger nucleases. The knockout rabbits had drastically elevated cholesterol and moderately increased triglyceride levels, mimicking symptoms in human heart disease. So far the rabbit genome has been successfully modified with three nuclease technologies. With a gestation period only days longer than those of rodents, we hope additional reports on their creation and characterization will help encourage the use of rabbit models where they are most relevant to human conditions. © 2014, Springer International Publishing Switzerland. Source


Hamilton S.M.,Baylor College of Medicine | Green J.R.,Baylor College of Medicine | Veeraragavan S.,Baylor College of Medicine | Yuva L.,Baylor College of Medicine | And 8 more authors.
Behavioral Neuroscience | Year: 2014

Animal models are critical for gaining insights into autism spectrum disorder (ASD). Despite their apparent advantages to mice for neural studies, rats have not been widely used for disorders of the human CNS, such as ASD, for the lack of convenient genome manipulation tools. Here we describe two of the first transgenic rat models for ASD, developed using zinc-finger nuclease (ZFN) methodologies, and their initial behavioral assessment using a rapid juvenile test battery. A syndromic and nonsyndromic rat model for ASD were created as two separate knockout rat lines with heritable disruptions in the genes encoding Fragile X mental retardation protein (FMRP) and Neuroligin3 (NLGN3). FMRP, a protein with numerous proposed functions including regulation of mRNA and synaptic protein synthesis, and NLGN3, a member of the neuroligin synaptic cell-adhesion protein family, have been implicated in human ASD. Juvenile subjects from both knockout rat lines exhibited abnormalities in ASD-relevant phenotypes including juvenile play, perseverative behaviors, and sensorimotor gating. These data provide important first evidence regarding the utility of rats as genetic models for investigating ASD-relevant genes. © 2014 American Psychological Association. Source


Brown A.J.,SAGE Labs | Fisher D.A.,SAGE Labs | Kouranova E.,SAGE Labs | McCoy A.,SAGE Labs | And 9 more authors.
Nature Methods | Year: 2013

Animal models with genetic modifications under temporal and/or spatial control are invaluable to functional genomics and medical research. Here we report the generation of tissue-specific knockout rats via microinjection of zinc-finger nucleases (ZFNs) into fertilized eggs. We generated rats with loxP-flanked (floxed) alleles and a tyrosine hydroxylase promoter-driven cre allele and demonstrated Cre-dependent gene disruption in vivo. Pronuclear microinjection of ZFNs, shown by our data to be an efficient and rapid method for creating conditional knockout rats, should also be applicable in other species. © 2013 Nature America, Inc. All rights reserved. Source

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