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Compensatory growth in novel Drosophila Akt1 mutants.

ABSTRACT: BACKGROUND:Organisms, tissues and cells are genetically programmed to grow to a specific largely pre-set size and shape within the appropriate developmental timing. In the event of mutation, cell death, or tissue damage, the remaining cells may increase their rate of growth to compensate and generate an intact, potentially smaller, tissue or organism in order to achieve the desired size. A delay in the developmental timing could aid in this process. The insulin receptor signalling pathway with its central component, the Akt1 kinase, and endpoint regulator, the transcription factor foxo, plays a significant role in the control of growth. Drosophila melanogaster is an excellent model organism with a well-studied life cycle and a consistently developing compound eye that can undergo analysis to compare changes in the properties of adult ommatidia as an indicator of growth. FINDINGS:Imprecise excision of a PZ P-element inserted in the upstream region of Akt1 generated several novel hypomorphic alleles with internally deleted regions of the Pelement. These mutations lead to small, viable Drosophila that present with delays in development. Suppression of this phenotype by the directed expression of Akt1 (+) indicates that the phenotypes observed are Akt1 dependent. Somatic clones of the eyes, consisting of homozygous tissue in otherwise heterozygous organisms that develop within a standard timeframe, signify that more severe phenotypes are masked by an extension in the time of development of homozygous mutants. Generation of Drosophila having the hypomorphic Akt1 alleles and a null allele of the downstream target foxo result in a phenotype very similar to that of the foxo mutant and do not resemble the Akt1 mutants. CONCLUSION:The developmental delay of these novel Akt1 hypomorphs results in a latent phenotype uncovered by generation of somatic clones. The compensatory growth occurring during the extended time of development appears to be implemented through alteration of foxo activity. Production of clones is an effective and informative way to observe the effects of mutations that result in small, viable, developmentally delayed flies.

SUBMITTER: Slade JD

PROVIDER: S-EPMC4372305 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Project description:Background: Skeletal muscle constitutes a significant portion of total body mass and is a major regulator of systemic metabolism as it serves as the major site for glucose disposal and the main reservoir for amino acids. With aging, cachexia, starvation, and myositis, there is a preferential loss of fast glycolytic muscle fibers. We previously reported a mouse model in which a constitutively-active Akt transgene is induced to express in a subset of muscle groups leading to the hypertrophy of type IIb myofibers with an accompanying increase in strength. This muscle growth protects mice in various cardio-metabolic disease models, but little is known about the underlying cellular and molecular mechanisms by which fast-twitch muscle impacts disease processes and regulates distant tissues. Purpose: In the present study, poly(A)+ tail mRNA-seq was performed to characterize the transcriptome of the hypertrophic gastrocnemius muscle from Akt1-transgenic mice. Results: Pathway analysis for the 3,481 differentially expressed genes in muscle identified enriched signaling pathways involving growth, cell cycle regulation, and inflammation. Combined metabolomics and transcriptomic analyses revealed that Akt1-induced muscle growth mediated a metabolic shift involving reductions in glycolysis and oxidative phosphorylation, but enhanced pentose phosphate pathway activation and increased branch chain amino acid accumulation. Signal peptide prediction analysis revealed 241 differentially expressed in muscle transcripts that potentially encode secreted proteins. A number of these secreted factors have signaling properties that are consistent with the myogenic, metabolic and cardiovascular-protective properties that have previously been associated with type IIb muscle growth. Conclusions: These data reveal that enhanced Akt signaling promotes the activation of the pentose phosphate and the accumulation of branched amino acids that are important for the production of nucleic acids and proteins. Numerous known and novel transcripts potentially encoding muscle secreted proteins were identified, indicating the importance of fast-twitch muscle in inter-tissue communication.

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Compensatory growth in novel Drosophila Akt1 mutants.

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