Tissue-specific and insulin-dependent expression of a pancreatic amylase gene in transgenic mice.

Osborn, Laurelee; Rosenberg, Michael K.; Keller, Scott A.; Meisler, Miriam H.

doi:10.1128/mcb.7.1.326

Cited by 71 publications

(53 citation statements)

References 55 publications

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“…Consequently, the continued presence of PDX1 in acinar cells may not be necessary for their function in the mature gland. Because efficient amylase gene transcription is dependent on insulin (35,36), the decrease of amylase mRNA accumulation may be an indirect effect mediated through decreased insulin production. Although the level of elastase enzyme is affected by long-term diabetes (37), elastase I gene transcription is not affected in the short term by insulin (38).…”

Section: Discussionmentioning

confidence: 99%

Experimental control of pancreatic development and maintenance

Holland

Hale

Kagami

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

214

182

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To investigate the role of the HOX-like homeoprotein PDX1 in the formation and maintenance of the pancreas, we have genetically engineered mice so that the only source of PDX1 is a transgene that can be controlled by the application of tetracycline or its analogue doxycycline. In these mice the coding region for the tetracyclineregulated transactivator (tTA off) has replaced the coding region of the endogenous Pdx1 gene to ensure correct temporal and spatial expression of the regulatable transactivator. In the absence of doxycycline, tTA off activates the transcription of a bicistronic transgene encoding PDX1 and an enhanced green fluorescent protein reporter, which acts as a visual marker of transgene expression in living cells. Expression of the transgene-encoded PDX1 rescues the Pdx1-null phenotype; the pancreata of these mice develop and function normally. The rescue is conditional; doxycycline-mediated repression of the transgenic Pdx1 throughout gestation recapitulates the Pdx1 null phenotype. Moreover, application of doxycycline at mid-pancreogenesis blocks further development. Adult animals of the rescue genotype that were treated with doxycycline for 3 weeks shut off Pdx1 expression, decreased insulin production, and lost the ability to maintain glucose homeostasis. These results demonstrate the feasibility of controlling the formation of an organ during embryogenesis in utero and the maintenance of the mature organ through the experimental manipulation of a key developmental regulator.

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Section: Discussionmentioning

confidence: 99%

Experimental control of pancreatic development and maintenance

Holland

Hale

Kagami

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

214

182

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“…To generate transgenic mice, the purified transgene fragment was microinjected into fertilized (C57BL͞6J ϫ C3H͞HeJ) F 1 mouse eggs as described (28). Tail DNA from mice born from injected embryos were screened for the presence of transgene by using Southern blot analysis.…”

Section: Generation Of Transgenic Mice Expressing Epha5 Dominant-negamentioning

confidence: 99%

Mistargeting hippocampal axons by expression of a truncated Eph receptor

Yue

Chen

Gale

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Topographic mapping of axon terminals is a general principle of neural architecture that underlies the interconnections among many neural structures. The Eph family tyrosine kinase receptors and their ligands, the ephrins, have been implicated in the formation of topographic projection maps. We show that multiple Eph receptors and ligands are expressed in the hippocampus and its major subcortical projection target, the lateral septum, and that expression of a truncated Eph receptor in the mouse brain results in a pronounced alteration of the hippocamposeptal topographic map. Our observations provide strong support for a critical role of Eph family guidance factors in regulating ontogeny of hippocampal projections.I nformation encoding as topographic maps, which reflects the spatial organization of sensory surfaces and body effectors, is a fundamental mechanism of nervous system function (1, 2). Such topographic representation is critically dependent on precise ordering of axon projections, which maintains the spatial organization of neurons in synaptic connections with target neurons. It has been suggested that topographic axon connections allow transfer of spatial information in the sensory systems (3). In the eye, retinal axons form an inverted projection map in the tectum, with dorsal axons projecting to the ventral tectum, and ventral axons to the dorsal tectum. Similarly, retinal ganglion neurons in the temporal and nasal sides send axons to the anterior and posterior regions of the tectum, respectively (4). Comparable mechanisms may also operate in the limbic circuits, where learning, memory, and emotional responses are elaborated. For example, the hippocampus sends axons topographically to the lateral septum, with dorsomedial neurons projecting to the dorsomedial area of the target, and ventrolateral neurons projecting to the ventrolateral septal region (5, 6). Similarity in organizational principles between limbic circuits and sensory systems suggests that learning, memory, and emotions may be governed by the same spatial constraints as sensory information processing.Based on analyses of regenerating retinal axons, Roger Sperry (7) proposed that axons and target neurons carry specific cytochemical identification tags, and that each axon makes synaptic connections only with neurons carrying matching affinity tags. These tags may be distributed as gradients in the projecting and target fields to specify topographic maps. Recent expression and functional studies suggest that ephrins and their receptors serve as the postulated chemoaffinity guidance tags. The ephrins are a family of cell surface molecules that are ligands of the Eph family tyrosine kinase receptors (8). The Eph receptors, EphA3 in the chicken and EphA5͞A6 in the mouse retina, are expressed in a nasal (low) to temporal (high) gradient (3, 9, 10). Complementary to the receptor gradient, the ligands ephrin-A2 and -A5 constitute an anterior (low) to posterior (high) gradient in the optic tectum (9, 11-13). Disruption of the ligand gradient by re...

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“…The pLCK/Myr-Akt2 construct was sequenced to ensure proper orientation of the insert. The insert containing the lck (lymphocyte speci®c kinase) promoter, Myr-Akt2, and the human growth hormone gene polyadenylation signal was isolated from the vector using NotI, puri®ed, and then microinjected into C57Bl/6J X C3H/HeJ F2 mouse oocytes as described previously (Ceci et al, 1989(Ceci et al, , 1991Osborn et al, 1987). To identify transgenic founder mice, genomic DNA was isolated from the tails of live-born weanling mice (Siracusa et al, 1987), DNA was digested to completion with SacI and analysed by Southern blotting using a 7700 bp probe obtained by KprI ± SacI digestion of pCMV/Akt2.…”

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confidence: 99%

Oncogenic transformation induced by membrane-targeted Akt2 and Akt3

et al. 2001

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The kinases Akt2, Akt3 and their myristylated variants, Myr-Akt2 and Myr-Akt3 were expressed by the RCAS vector in chicken embryo ®broblasts (CEF). Myr-Akt2 and Myr-Akt3 were strongly oncogenic, inducing multilayered foci of transformed cells. In contrast, wild-type Akt2 and Akt3 were only poorly transforming, their e ciencies of focus formation were more than 100-fold lower; foci appeared later and showed less multilayering. Addition of the myristylation signal not only enhanced oncogenic potential but also increased kinase activities. Myr-Akt2 and Myr-Akt3 also induced hemangiosarcomas in the animal, whereas wild type Akt2 and Akt3 were not oncogenic in vivo. Furthermore, Akt2, driven by the lck (lymphocyte speci®c kinase) promoter in transgenic mice, induced lymphomas. The oncogenic e ects of Akt2 and Akt3 described here are indistinguishable from those of Akt1. The downstream targets relevant to oncogenic transformation are therefore probably shared by the three Akt kinases. Oncogene (2001) 20, 4419 ± 4423.

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Tissue-specific and insulin-dependent expression of a pancreatic amylase gene in transgenic mice.

Cited by 71 publications

References 55 publications

Experimental control of pancreatic development and maintenance

Experimental control of pancreatic development and maintenance

Mistargeting hippocampal axons by expression of a truncated Eph receptor

Oncogenic transformation induced by membrane-targeted Akt2 and Akt3

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