糖尿病相关错误折叠人胰岛素原果蝇模型的遗传复杂性
Genetic Complexity in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin
摘要：
在这里，我们使用果蝇创建一个人类永久性新生儿糖尿病的遗传模型，目前的实验结果描述这种复杂性的尺寸。该方法涉及人前胰岛素原的错误折叠突变体hINSC 96 Y的转基因表达，这是该疾病的原因。当在果蝇成虫盘中表达时，hINSC96 Y引起成虫结构的减少，包括眼睛、翅膀和背。眼的视象盘在小眼的结构和排列上都有缺陷。在翅膀中，hINSC 96 Y的表达导致静脉和机械感觉器官的异位表达，表明调节细胞命运的野生型信号传导过程的破坏。这些易于测量的疾病表型对温度、基因剂量和性别敏感。突变型（而非野生型）胰岛素原在眼胚盘中的表达诱导IRE 1介导的Xbp 1可变剪接（内质网应激反应激活的信号），并产生基因表达的整体变化。突变hINS转基因试验菌株与果蝇遗传参考组的原种杂交时，产生具有连续疾病表型范围和大的广义遗传力的F1成虫。令人惊讶的是，在这些杂交中，突变hINS诱导的眼部疾病的严重程度与背中的严重程度不相关，也与由两种显性眼部突变体的表达引起的眼部减少表型不相关，所述两种显性眼部突变体在两种不同的眼部发育途径中起作用，当杂交到相同的遗传背景中时，为Drop（Dr）或Lobe（L）。因此，突变hINS诱导的疾病的遗传变异性的组织特异性具有其自身独特的特征。疾病特异性表型变异的遗传优势使得这种方法适合于在自然变异的简单F1筛选中的全基因组关联研究（GWAS）。
英文摘要：
Here we use Drosophila melanogaster to create a genetic model of human permanent neonatal diabetes mellitus and present experimental results describing dimensions of this complexity. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINSC96Y, which is a cause of the disease. When expressed in fly imaginal discs, hINSC96Y causes a reduction of adult structures, including the eye, wing and notum. Eye imaginal discs exhibit defects in both the structure and arrangement of ommatidia. In the wing, expression of hINSC96Y leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild type signaling processes regulating cell fates. These readily measurable disease phenotypes are sensitive to temperature, gene dose and sex. Mutant (but not wild type) proinsulin expression in the eye imaginal disc induces IRE1-mediated Xbp1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel produces F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease thus has its own distinct signature. The genetic dominance of disease-specific phenotypic variability makes this approach amenable to genome-wide association study (GWAS) in a simple F1 screen of natural variation.
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