MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.
Earlham Institute, Norwich Research Park, Norwich, NR4 7UG, United Kingdom.
Sci Rep. 2019 Jan 24;9(1):485. doi: 10.1038/s41598-018-37284-1.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease whose underpinning molecular mechanisms and neural substrates are subject to intense scrutiny. Interestingly, the cerebellum has emerged as one of the key brain regions affected in ASD. However, the genetic and molecular mechanisms that link the cerebellum to ASD, particularly during development, remain poorly understood. To gain insight into the genetic and molecular mechanisms that might link the cerebellum to ASD, we analysed the transcriptome dynamics of a developing cell population highly enriched for Purkinje cells of the mouse cerebellum across multiple timepoints. We identified a single cluster of genes whose expression is positively correlated with development and which is enriched for genes associated with ASD. This ASD-associated gene cluster was specific to developing Purkinje cells and not detected in the mouse neocortex during the same developmental period, in which we identified a distinct temporally regulated ASD gene module. Furthermore, the composition of ASD risk genes within the two distinct clusters was significantly different in their association with intellectual disability (ID), consistent with the existence of genetically and spatiotemporally distinct endophenotypes of ASD. Together, our findings define a specific cluster of ASD genes that is enriched in developing PCs and predicts co-morbidity status.
自闭症谱系障碍（ASD）是一种复杂的神经发育性疾病，其潜在的分子机制和神经基质受到了广泛关注。有趣的是，小脑已成为 ASD 受影响的关键大脑区域之一。然而，将小脑与 ASD 联系起来的遗传和分子机制，特别是在发育过程中，仍然知之甚少。为了深入了解可能将小脑与 ASD 联系起来的遗传和分子机制，我们分析了在多个时间点高度富集浦肯野细胞的发育细胞群体的转录组动态。我们确定了一个单一的基因簇，其表达与发育呈正相关，并且富含与 ASD 相关的基因。这个与 ASD 相关的基因簇是发育中的浦肯野细胞所特有的，而在同一发育时期的小鼠新皮层中并未检测到，在该时期我们鉴定出了一个独特的、受时间调控的 ASD 基因模块。此外，两个不同簇中 ASD 风险基因的组成在与智力障碍（ID）的关联上有显著差异，这与 ASD 的遗传和时空上不同的表型存在一致。总之，我们的研究结果定义了一个与 ASD 相关的特定基因簇，该基因簇在发育中的浦肯野细胞中富集，并预测了共病状态。
