Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of transgenic mice constitutively active for caPI3K and dominant-negative forms of PI3K (dnPI3K) to test if the insulin/IGF-IRS-PI3K-Akt determines organ size in vertebrates

ABSTRACT: The insulin/IGF-IRS-PI3K-Akt pathway is highly conserved in evolution. To test whether this signaling cascade determines organ size in vertebrates, we have recently created mouse lines transgenic for constitutively active (caPI3K) and dominant-negative forms of PI3K (dnPI3K) (Shioi et al., 2000). Transgene expression is driven by the cardiac-specific a -myosin heavy chain (MHC) promoter. Both transgenic lines are characterized by moderate but highly consistent changes in heart size, despite the fact that body weight and the size of other organs are completely normal. caPI3K transgenic animals have hearts 20% larger than those of wild type littermates, whereas dnPI3K mice have hearts that are 17% smaller. The observed changes in heart size correlate with an appropriate increase or decrease in the size of transgenic cardiomyocytes. These hearts do not have cardiomyopathic changes, since the contractile function of transgenic hearts is normal, and signs of necrosis, apoptosis, or interstitial fibrosis are absent (see Physiology). These data suggest an autonomous role for PI3K in cell size regulation. Our goal is now to determine how activation of this system translates into changes in cell size by identifying the trigger and components of this signaling cascade. Heterozygous caPI3K (constitutively active PI3K) and dnPI3K (dominant-negative PI3K) transgenic female mice (5-14 months) compared with non-transgenic littermates. Transgene expression driven by the a -myosin heavy chain (a -MHC) promoter.

ORGANISM(S): Mus musculus

SUBMITTER: Martina Schinke

PROVIDER: E-GEOD-558 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:CUG-BP, Elav-like family (CELF) proteins regulate alternative splicing. In MHC-CELFdelta transgenic mice, CELF-mediated alternative splicing is disrupted in heart muscle via expression of a nuclear dominant negative CELF protein under an alpha-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy and contractile dysfunction by 3 weeks of age, shortly after the transgene is activated and splicing defects appear. Cardiac function and heart size spontaneously recover with age in a low-expressing (mild) line of MHC-CELFdelta mice despite persistence of dominant negative protein expression and splicing defects, whereas there is no recovery in a higher-expressing (severe) line that also experiences early muscle death and fibrosis. In this study, we explored the basis for this functional recovery by comparing the gene expression profiles in the hearts of low- and high-expressing lines of MHC-CELFdelta mice to those of wild type littermates at 3 weeks (when cardiac dysfunction is maximal) and 24 weeks (when the low-expressing line has recovered) using microarrays. We found that differences in gene expression are greatly reduced in older animals from the low-expressing line, but were exacerbated in the high-expressing line. We did not find evidence of a new compensatory pathway being activated in the low-expressing line with age, and propose that recovery may occur due to developmental stage-specific compatibility of CELF-dependent splice variants with the changing cellular environment of cardiomyocytes. Microarray analysis was performed on total RNA extracted from whole hearts of female mice: three MHC-CELFdelta-10 (high-expressing line) and three MHC-CELFdelta-574 (low-expressing line) were collected at 3 weeks, and five MHC-CELFdelta-10 and five MHC-CELFdelta-574 were collected at 24 weeks. Two wild type mice from each line were collected at each time point (n = 4 total wild type at 3 weeks, and n = 4 total wild type at 24 weeks).

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Transcription profiling of transgenic mice constitutively active for caPI3K and dominant-negative forms of PI3K (dnPI3K) to test if the insulin/IGF-IRS-PI3K-Akt determines organ size in vertebrates

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