Gt(ROSA)26Sor
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Gt(ROSA)26Sor -gene trap ROSA 26, Philippe Soriano
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Divergent cell cycle kinetics of midgestation ventricular cells entail a higher engraftment efficiency after cell transplantation.
Journal: American journal of physiology. Cell physiology
March/19/2015
Description

Cardiac progenitor cells (CPCs) in the primary and secondary heart fields contribute to the formation of all major cell types in the mammalian heart. While some CPCs remain undifferentiated in midgestation and postnatal hearts, very little is known about their proliferation and differentiation potential. In this study, using an Nkx2.5 cell lineage-restricted reporter mouse model, we provide evidence that Nkx2.5(+) CPCs and cardiomyocytes can be readily distinguished from nonmyocyte population using a combination of Nkx2.5 and sarcomeric myosin staining of dispersed ventricular cell preparations. Assessment of cell number and G1/S transit rates during ventricular development indicates that the proliferative capacity of Nkx2.5(+) cell lineage gradually decreases despite a progressive increase in Nkx2.5(+) cell number. Notably, midgestation ventricles (E11.5) contain a larger number of CPCs (∼2-fold) compared with E14.5 ventricles, and the embryonic CPCs retain cardiomyogenic differentiation potential. The proliferation rates are consistently higher in embryonic CPCs compared with myocyte population in both E11.5 and E14.5 ventricles. Results from two independent cell transplantation models revealed that E11.5 ventricular cells with a higher percentage of proliferating CPCs can form larger grafts compared with E14.5 ventricular cells. Furthermore, transplantation of embryonic ventricular cells did not cause any undesirable side effects such as arrhythmias. These data underscore the benefits of donor cell developmental staging in myocardial repair.

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Pubmed
Circulating Ghrelin Acts on GABA Neurons of the Area Postrema and Mediates Gastric Emptying in Male Mice.
Journal: Endocrinology
July/26/2017
Description

Ghrelin is known to act on the area postrema (AP), a sensory circumventricular organ located in the medulla oblongata that regulates a variety of important physiological functions. However, the neuronal targets of ghrelin in the AP and their potential role are currently unknown. In this study, we used wild-type and genetically modified mice to gain insights into the neurons of the AP expressing the ghrelin receptor [growth hormone secretagogue receptor (GHSR)] and their role. We show that circulating ghrelin mainly accesses the AP but not to the adjacent nucleus of the solitary tract. Also, we show that both peripheral administration of ghrelin and fasting induce an increase of c-Fos, a marker of neuronal activation, in GHSR-expressing neurons of the AP, and that GHSR expression is necessary for the fasting-induced activation of AP neurons. Additionally, we show that ghrelin-sensitive neurons of the AP are mainly γ-aminobutyric acid (GABA)ergic, and that an intact AP is required for ghrelin-induced gastric emptying. Overall, we show that the capacity of circulating ghrelin to acutely induce gastric emptying in mice requires the integrity of the AP, which contains a population of GABA neurons that are a target of plasma ghrelin.

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Pubmed
Numb is required to prevent p53-dependent senescence following skeletal muscle injury.
Journal: Nature communications
May/10/2016
Description

Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue. Here we inactivate the endocytic adaptor protein Numb in skeletal muscle stem cells prior to chronic or severe muscle injury in mice. We observe two types of senescence in regenerating muscle; a transient senescence in non-myogenic cells of control and Numb mutant mice that partly depends on INK4a/ARF activity, and a persistent senescence in myogenic cells lacking Numb. The senescence levels of Numb-deficient muscle is reduced to wild type levels by an anti-oxidant treatment or p53 ablation, resulting in functional rescue of the regenerative potential in Numb mutants. Ex vivo experiments suggest that Numb-deficient senescent cells recruit macrophages to sustain inflammation and drive fibrosis, two hallmarks of the impaired muscle regeneration in Numb mutants. These findings provide insights into previously reported developmental and oncogenic senescence that are also differentially regulated by p53.

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Pubmed
Local Cre-mediated gene recombination in vascular smooth muscle cells in mice.
Journal: Transgenic research
April/13/2009
Description

Here we describe a means to conditionally modify genes at a predefined and localized region of the vasculature using a perivascular drug delivery device (PDD). A 4-hydroxytamoxifen (4-OHT)-eluting PDD was applied around the carotid or femoral artery of a mouse strain carrying both the tamoxifen-inducible and smooth muscle cell (SMC)-specific Cre-recombinase (SM-Cre-ER(T2)) transgene and a stop-floxed beta-galactosidase gene in the Rosa26 locus: the SM-CreER(T2)(ki)/rosa26 mouse. A dose and time curve of 0-10% (w/w) 4-OHT and 0-14 days application of the PDD in SM-CreER(T2)(ki)/rosa26 mice showed optimal gene recombination at 1% (w/w) 4-OHT loading at 7 days post application (carotid artery 2.4+/-1.8%; femoral artery 4.0+/-3.8% of SMCs). The unique 4-OHT-eluting PDD allowed us to achieve SMC-specific recombination in the same order of magnitude as compared to systemic tamoxifen administration. In addition, recombination was completely confined to the PDD-treated vessel wall segment. Thus, local application of a 4-OHT-eluting PDD results in vascular SMC-specific Cre-mediated recombination in SM-CreER(T2)(ki)/rosa26 mice without affecting additional SMCs.

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Pubmed
Targeting iCre expression to murine progesterone receptor cell-lineages using bacterial artificial chromosome transgenesis.
Journal: Genesis (New York, N.Y. : 2000)
February/20/2007
Description

Gene-targeting in embryonic stem cells has been the dominant genetic approach when engineering mouse models to query the physiologic importance of the progesterone receptor (PR). Although these models have been instrumental in disclosing the in vivo significance of the progesterone signaling pathway, generation of such mice exacts considerable expenditure of time, effort, and expense. Considering the growing list of new PR mouse models that are urgently required to address the next questions in progestin biology, bacterial artificial chromosome (BAC) recombineering in conjunction with transgenesis was evaluated as an alternative method to accelerate the creation of these models in the future. Using this approach, we describe the generation of three PR-BAC(iCre) transgenic lines in which improved Cre recombinase (iCre) was targeted in-frame, downstream, and under the control of the PR promoter contained within a BAC transgene. Crossing with the ROSA26R revealed that the PR-BAC(iCre) transgenic expresses active iCre only in cell-lineages that express the PR. The specificity of the PR-BAC(iCre) transgene not only underscores the importance of BAC-mediated transgenesis as a quick, easy, and affordable method by which to engineer the next generation of PR mouse models, but also provides a unique opportunity to investigate transcriptional control of PR expression as well as PR structure-function relationships in vivo.

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Pubmed
In vivo overactivation of the Notch signaling pathway in the developing cochlear epithelium.
Journal: Hearing research
June/5/2016
Description

Notch signaling is thought to play important roles in both prosensory domain specification and cell fate determination during inner ear development. Inhibition of the Notch signaling pathway in prosensory cells results in excessive hair cell formation, while activation of the Notch signaling pathway by overexpression of activated Notch1 (Notch1-intercellular domain, NICD) in the cochlear epithelium results in ectopic sensory patches where NICD is expressed. However, the effect of Notch activation on the prosensory domain is not fully understood. To elucidate the precise roles of Notch signaling in cochlear prosensory epithelium we examined the effects of Notch overactivation on cochlear prosensory cells of transgenic mice with conditional NICD expression. The histology of the cochlear epithelium was investigated in these mice. The cochlear duct of conditional NICD embryos was wide and short, and the epithelium formed an abnormal tubular structure. Hair cell numbers were reduced though some hair cells developed where NICD was overexpressed. The decrease in hair cells was not accompanied by Hes5-positive and Prox1-positive supporting cell overproduction. Ectopic expression of early prosensory markers, such as Jag1 and Hes/Hey genes, was observed but no expression of Hes5 was found. Our data shows that NICD overexpression disrupts the extension of cochlear epithelium, and reduces the total numbers of hair cells and supporting cells in the sensory epithelium. Thus, an appropriate level of Notch signaling is needed for the normal extension of the cochlear epithelium and for differentiation of both hair cells and supporting cells.

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Pubmed
The NF-κB regulator Bcl-3 governs dendritic cell antigen presentation functions in adaptive immunity.
Journal: Journal of immunology (Baltimore, Md. : 1950)
March/2/2015
Description

Bcl-3 is an atypical member of the IκB family and modulates gene expression via interaction with p50/NF-κB1 or p52/NF-κB2 homodimers. We report in the present study that Bcl-3 is required in dendritic cells (DCs) to assure effective priming of CD4 and CD8 T cells. Lack of Bcl-3 in bone marrow-derived DCs blunted their ability to expand and promote effector functions of T cells upon Ag/adjuvant challenge in vitro and after adoptive transfers in vivo. Importantly, the critical role of Bcl-3 for priming of T cells was exposed upon Ag/adjuvant challenge of mice specifically ablated of Bcl-3 in DCs. Furthermore, Bcl-3 in endogenous DCs was necessary for contact hypersensitivity responses. Bcl-3 modestly aided maturation of DCs, but most consequentially, Bcl-3 promoted their survival, partially inhibiting expression of several antiapoptotic genes. Loss of Bcl-3 accelerated apoptosis of bone marrow-derived DCs during Ag presentation to T cells, and DC survival was markedly impaired in the context of inflammatory conditions in mice specifically lacking Bcl-3 in these cells. Conversely, selective overexpression of Bcl-3 in DCs extended their lifespan in vitro and in vivo, correlating with increased capacity to prime T cells. These results expose a previously unidentified function for Bcl-3 in DC survival and the generation of adaptive immunity.

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Pubmed
Modeling synovial sarcoma: timing is everything.
Journal: Cancer cell
May/14/2007
Description

Synovial sarcoma is characterized by the presence of a fusion protein involving SYT and SSX2. In this issue of Cancer Cell, Haldar et al. have genetically engineered a mouse model of this disease. They show that expression of the SYT-SSX2 fusion gene yields a highly penetrant and representative model of human synovial sarcoma, but only if expression occurs in a particular biologic context. The mouse model will be a valuable resource for studying tumor biology but is also a striking example of how important understanding of normal tissue and developmental biology is to our understanding of cancer.

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Pubmed
DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment.
Journal: PLoS genetics
May/11/2017
Description

Male mammals produce sperm for most of postnatal life and therefore require a robust germ line stem cell system, with precise balance between self-renewal and differentiation. Prior work established doublesex- and mab-3-related transcription factor 1 (Dmrt1) as a conserved transcriptional regulator of male sexual differentiation. Here we investigate the role of Dmrt1 in mouse spermatogonial stem cell (SSC) homeostasis. We find that Dmrt1 maintains SSCs during steady state spermatogenesis, where it regulates expression of Plzf, another transcription factor required for SSC maintenance. We also find that Dmrt1 is required for recovery of spermatogenesis after germ cell depletion. Committed progenitor cells expressing Ngn3 normally do not contribute to SSCs marked by the Id4-Gfp transgene, but do so when spermatogonia are chemically depleted using busulfan. Removal of Dmrt1 from Ngn3-positive germ cells blocks the replenishment of Id4-GFP-positive SSCs and recovery of spermatogenesis after busulfan treatment. Our data therefore reveal that Dmrt1 supports SSC maintenance in two ways: allowing SSCs to remain in the stem cell pool under normal conditions; and enabling progenitor cells to help restore the stem cell pool after germ cell depletion.

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Pubmed
Integration of H-2Z1, a somatosensory cortex-expressed transgene, interferes with the expression of the Satb1 and Tbc1d5 flanking genes and affects the differentiation of a subset of cortical interneurons.
Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience
August/2/2012
Description

H-2Z1 is an enhancer trap transgenic mouse line in which the lacZ reporter delineates the somatosensory area of the cerebral cortex where it is expressed in a subset of layer IV neurons. In the search of somatosensory specific genes or regulatory sequences, we mapped the H-2Z1 transgene insertion site to chromosome 17, 100 and 460 kb away from Tbc1d5 and Satb1 flanking genes. We show here that insertion of the H-2Z1 transgene results in three distinct outcomes. First, a genetic background-sensitive expression of lacZ in several brain and body structures. While four genes in a 1 Mb region around the insertion are expressed in the barrel cortex, H-2Z1 expression resembles more that of its two direct neighbors. Moreover, H-2Z1 closely reports most of the body and brain expression sites of the Satb1 chromatin remodeling gene including tooth buds, thymic epithelium, pontine nuclei, fastigial cerebellar nuclei, and cerebral cortex. Second, the H-2Z1 transgene causes insertional mutagenesis of Tbc1d5 and Satb1, leading to a strong decrease in their expressions. Finally, insertion of H-2Z1 affects the differentiation of a subset of cortical GABAergic interneurons, a possible consequence of downregulation of Satb1 expression. Thus, the H-2Z1 "somatosensory" transgene is inserted in the regulatory landscape of two genes highly expressed in the developing somatosensory cortex and reports for a subdomain of their expression profiles. Together, our data suggest that regulation of H-2Z1 expression results from local and remote genetic interactions.

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