Mosaic expression of an Hprt transgene integrated in a region of Y heterochromatin

Pravtcheva, Dimitrina D.; Wise, Thomas L.; Ensor, Nancy J.; Ruddle, Frank H.

doi:10.1002/jez.1402680606

Cited by 23 publications

(8 citation statements)

References 88 publications

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“…In addition, mosaic staining of the ATF3 transgene expression was observed in cardiomyocytes by immunohistochemistry. This is a relatively common phenomenon in transgenic mice and is thought to be due to the position effect of the transgene [23]. Nevertheless, the ATF3 protein was barely detectable by Western blot analysis using either an anti-ATF3 or anti-HA antibodies.…”

Section: Discussionmentioning

confidence: 99%

Adult Cardiac Expression of the Activating Transcription Factor 3, ATF3, Promotes Ventricular Hypertrophy

et al. 2013

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Cardiac hypertrophy is an adaptive response to various mechanophysical and pathophysiological stresses. However, when chronic stress is sustained, the beneficial response turns into a maladaptive process that eventually leads to heart failure. Although major advances in the treatment of patients have reduced mortality, there is a dire need for novel treatments for cardiac hypertrophy. Accordingly, considerable efforts are being directed towards developing mice models and understanding the processes that lead to cardiac hypertrophy. A case in point is ATF3, an immediate early transcription factor whose expression is induced in various cardiac stress models but has been reported to have conflicting functional significance in hypertrophy. To address this issue, we generated a transgenic mouse line with tetracycline-regulated ATF3 cardiac expression. These mice allowed us to study the consequence of ATF3 expression in the embryo or during the adult period, thus distinguishing the effect of ATF3 on development versus pathogenesis of cardiac dysfunction. Importantly, ATF3 expression in adult mice resulted in rapid ventricles hypertrophy, heart dysfunction, and fibrosis. When combined with a phenylephrine-infusion pressure overload model, the ATF3 expressing mice displayed a severe outcome and heart dysfunction. In a complementary approach, ATF3 KO mice displayed a lower level of heart hypertrophy in the same pressure overload model. In summary, ectopic expression of ATF3 is sufficient to promote cardiac hypertrophy and exacerbates the deleterious effect of chronic pressure overload; conversely, ATF3 deletion protects the heart. Therefore, ATF3 may serve as an important drug target to reduce the detrimental consequences of heart hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Adult Cardiac Expression of the Activating Transcription Factor 3, ATF3, Promotes Ventricular Hypertrophy

et al. 2013

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“…However, random shutoff of transgene expression has been noted frequently in genetically modified eukaryotes (Milot et al, 1996;Pravtcheva et al, 1994). Random transgene silencing by heterochromatin has been attributed to a phenomenon called position effect variegation (Allshire et al, 1994;Festenstein et al, 1996;Robertson et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Development of a macromolecular diffusion pathway in the lens

Shestopalov

Bassnett

2003

Journal of Cell Science

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The mammalian lens consists of an aged core of quiescent cells enveloped by a layer of synthetically active cells. Abundant gap junctions within and between these cell populations ensure that the lens functions as an electrical syncytium and facilitates the exchange of small molecules between surface and core cells. In the present study, we utilized an in vivo mouse model to characterize the properties of an additional pathway, permeable to macromolecules, which co-exists with gap-junction-mediated communication in the lens core. The TgN(GFPU)5Nagy strain of mice carries a green fluorescent protein (GFP) transgene. In the lenses of hemizyous animals, GFP was expressed in a variegated fashion, allowing diffusion of GFP to be visualized directly. Early in development, GFP expression in scattered fiber cells resulted in a checkerboard fluorescence pattern in the lens. However, at E15 and later, the centrally located fiber cells became uniformly fluorescent. In the adult lens, a superficial layer of cells, approximately 100 μm thick, retained the original mosaic fluorescence pattern, but the remainder, and majority, of the tissue was uniformly fluorescent. We reasoned that at the border between the two distinct labeling patterns, a macromolecule-permeable intercellular pathway was established. To test this hypothesis, we microinjected 10 kDa fluorescent dextran into individual fiber cells and followed its diffusion by time-lapse microscopy. Injections at depths of >100 μm resulted in intercellular diffusion of dextran from injected cells. By contrast, when injections were made into superficial fiber cells, the injected cell invariably retained the dextran. Together, these data suggest that, in addition to being coupled by gap junctions, cells in the lens core are interconnected by a macromolecule-permeable pathway. At all ages examined, a significant proportion of the nucleated fiber cell population of the lens was located within this region of the lens.

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“…This most specialized mouse chromosome consists predominantly of highly repeated DNA sequences with no obvious function (Bishop, 1993). Additionally, because of its extremely late replication during mitosis, characteristic of heterochromatic segments, an optimal expression of transgenes on the mouse Y-chromosome may not be expected (Pravtcheva et al 1994). X-chromosomal integrated transgenes can be subjected to modifications similar to those reported for endogenous X-linked genes.…”

Section: Position Effects On Transgene Expressionmentioning

confidence: 99%