Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.
Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.
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DOI：
10.1038/mp.2015.17
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发表时间：
2016-01
影响因子：
11
通讯作者：
Eng C
中科院分区：
文献类型：
--
作者：
Tilot AK;Bebek G;Niazi F;Altemus JB;Romigh T;Frazier TW;Eng C
自闭症谱系障碍(ASD)是一种神经发育疾病，具有明确但不同的遗传成分。肿瘤抑制基因PTEN的胚系突变是ASD合并大头畸形的公认风险因素，条件性PTEN小鼠模型损害了社会行为和大脑发育。在患者中观察到的一些突变破坏了PTEN蛋白正常平衡的核质定位，我们开发了Ptenm3M4模型来研究细胞质占优势的Pten的影响。在这个模型中，Pten的胚系错误定位导致学习和记忆完好的不适当的社会行为，这一特征使人想起高功能自闭症。这些动物还表现出神经炎症的组织学证据，以及6周大时神经胶质细胞数量的扩张。我们假设，这个模型的神经转录组将以一种可以告知人类特发性ASD的方式发生改变，这是一种体质状况。使用总RNA测序，我们发现Ptenm3m4小鼠从两周到六周的神经基因表达逐渐中断，涉及免疫和突触途径。这些变化包括许多高度共表达的人类ASD易感基因的下调。与人类皮质发育相比较，共表达网络显示，在Ptenm3m4小鼠中被破坏的基因与人类ASD的基因在相同的区域富含。虽然PTEN相关的ASD相对少见，但我们的观察表明，Ptenm3m4模型概括了人类ASD的多种分子特征，并且Pten在ASD发病机制中的共同途径的上游发挥作用。
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor PTEN are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the PTEN protein, and we developed the Ptenm3m4 model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by six-weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA-sequencing, we found progressive disruption of neural gene expression in Ptenm3m4 mice from two- to six-weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly co-expressed human-ASD-susceptibility genes. Comparison to a human cortical development coexpression network revealed that genes disrupted in Ptenm3m4 mice were enriched in the same areas as those of human ASD. While PTEN-related ASD is relatively uncommon, our observations suggest that the Ptenm3m4 model recapitulates multiple molecular features of human-ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.