English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

Here we use Drosophila melanogaster to create a genetic model of humanpermanent neonatal diabetes mellitus and present experimental resultsdescribing dimensions of this complexity. The approach involves the transgenicexpression of a misfolded mutant of human preproinsulin, hINSC96Y, which is acause of the disease. When expressed in fly imaginal discs, hINSC96Y causes areduction of adult structures, including the eye, wing and notum. Eye imaginaldiscs exhibit defects in both the structure and arrangement of ommatidia. Inthe wing, expression of hINSC96Y leads to ectopic expression of veins andmechano-sensory organs, indicating disruption of wild type signaling processesregulating cell fates. These readily measurable disease phenotypes aresensitive to temperature, gene dose and sex. Mutant (but not wild type)proinsulin expression in the eye imaginal disc induces IRE1-mediated Xbp1alternative splicing, a signal for endoplasmic reticulum stress responseactivation, and produces global change in gene expression. Mutant hINStransgene tester strains, when crossed to stocks from the Drosophila GeneticReference Panel produces F1 adults with a continuous range of diseasephenotypes and large broad-sense heritability. Surprisingly, the severity ofmutant hINS-induced disease in the eye is not correlated with that in the notumin these crosses, nor with eye reduction phenotypes caused by the expression oftwo dominant eye mutants acting in two different eye development pathways, Drop(Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissuespecificity of genetic variability for mutant hINS-induced disease thus has itsown distinct signature. The genetic dominance of disease-specific phenotypicvariability makes this approach amenable to genome-wide association study(GWAS) in a simple F1 screen of natural variation.

Genetic Complexity in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin