A gene expression signature in developing Purkinje cells predicts autism and intellectual disability co-morbidity status

Abstract

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.

Functional Outcomes of Cerebellar Malformations

“…Linking the findings of reduced cerebellar gray matter, the elaboration of the cerebellum in the perinatal period, and aberrant functional connectivity in ASD, recent transcriptomic profiling of Purkinje cells during development found that there is an enrichment of genes associated with ASD (Clifford et al, 2019). Interestingly, when compared to ASD-associated genes expressed during neocortical development, those in the Purkinje cell cluster were less likely to be associated with comorbid intellectual disability (Clifford et al, 2019). How this finding fits with other analyses linking high functioning, but not low functioning, ASD with cerebellar pathology warrants additional investigation (Noonan et al, 2009; Scott et al, 2009; Khan et al, 2015).…”

Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila

“…Interestingly, although the cerebellum has classically been associated with motor function, there is increasing evidence for its role in cognition (Leiner et al, 1993; Vandervert, 2016) and as a key region in ASD susceptibility (Chen et al, 2017; Peter et al, 2016; Wang et al, 2014). This association has, however, been attributed to dysfunction of Purkinje cells (Box 1) (Clifford et al, 2019; Tsai et al, 2012), for which no correlate has been identified in Drosophila , thus limiting studies into this interesting topic.…”

Abnormal Cerebellar Development in Autism Spectrum Disorders

“…Interestingly, many of the monogenic, mendelian-inherited ASD genes have a high coexpression in the cerebellum. This growing list of genes includes, but is not limited to, SHANK2 and SHANK3, TSC1 and TSC2, and AUTS2 [4][5][6].…”