Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice
Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice
复制标题
DOI：
10.1093/hmg/ddr300
复制
发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Hamilton, Bruce A.
中科院分区：
文献类型：
--
作者：
Alcaraz, Wendy A.;Chen, Edward;Hamilton, Bruce A.
神经回路的发育取决于信号通路的整合，以在正确的时间、正确的地点协调正确数量的细胞类型的规范、增殖和分化。锌指蛋白 423 (Zfp423) 是一种 30 锌指转录因子，与多种发育信号通路的成分形成交替复合物，表明它是大脑发育过程中的信号整合点。我们之前表明，缺乏 Zfp423 的小鼠小脑前体细胞增殖减少，导致蚓部完全丧失和小脑半球不同程度的发育不全。在这里，我们表明 Zfp423(-/)-半球畸形是由遗传和非遗传因素共同塑造的，在不同的近交遗传背景下产生不同的表型分布。在遗传图谱研究中，我们确定了四个加性修饰基因座 (Amzn1-4) 和七个综合相互作用基因座 (Smzn1.1-3.1)，它们共同解释了大约三分之一的表型方差。菌株特异性序列多态性和表达数据提供了每个修饰基因座的功能变异候选基因的精简列表。环境协变量仅增加了适度的解释力，表明存在额外的随机成分。这些结果提供了对后脑畸形模型中表型变异来源的全面分析。
Development of neural circuitry depends on the integration of signaling pathways to coordinate specification, proliferation and differentiation of cell types in the right number, in the right place, at the right time. Zinc finger protein 423 (Zfp423), a 30-zinc finger transcription factor, forms alternate complexes with components of several developmental signaling pathways, suggesting it as a point of signal integration during brain development. We previously showed that mice lacking Zfp423 have reduced proliferation of cerebellar precursor cells, resulting in complete loss of vermis and variable hypoplasia of cerebellar hemispheres. Here, we show that Zfp423(-/)-hemisphere malformations are shaped by both genetic and non-genetic factors, producing distinct phenotype distributions in different inbred genetic backgrounds. In genetic mapping studies, we identify four additive modifier loci (Amzn1-4) and seven synthetically interacting loci (Smzn1.1-3.1) that together explain approximately one-third of the phenotypic variance. Strain-specific sequence polymorphism and expression data provide a reduced list of functional variant candidate genes at each modifier locus. Environmental covariates add only modest explanatory power, suggesting an additional stochastic component. These results provide a comprehensive analysis of sources of phenotype variation in a model of hindbrain malformation.