Segregated expressions of autism risk genes Cdh11 and Cdh9 in autism-relevant regions of developing cerebellum

Wang, Chunlei; Pan, Yi-Hsuan; Wang, Yue; Blatt, Gene J.; Yuan, Xiaobin

doi:10.1186/s13041-019-0461-4

Cited by 24 publications

(19 citation statements)

References 88 publications

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“…It is likely that cadherins, Cdh11 in particular, may play important roles in mediating synapse formation during the wiring of circuits in these brain areas. Consistent with this postulation, our recent work showed Cdh11 expression in ASD-associated sub-regions in the CB of developing mouse brain 58 .…”

Section: Multiple Members Of the Cadherin Family As Risk Factors For Asdsupporting

confidence: 79%

Association ofCDH11with ASD revealed by matched-gene co-expression analysis and mouse behavioral studies

Wang

Jia

et al. 2020

Preprint

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Genetic variants of a large group of susceptibility genes have been associated with similar clinical manifestations of autism spectrum disorders (ASD), suggesting convergent function of these genes during brain development. Gene co-expression analysis has emerged as an important tool to identify convergent molecular pathways shared by ASD risk genes. In this study, four gene features, including gene size, mRNA length, mRNA abundance, and guanine-cytosine content, were found to profoundly affect gene co-expression. A new method termed "matched-gene coexpression analysis" (MGCA) was developed to screen for biologically meaningful gene coexpression relationships, taking into the consideration of the effect of these features on gene coexpression. With this method, significant convergence of the expression of high-confidence ASD risk genes (hcASDs) in the brain was demonstrated, and an improved efficacy in the prediction of convergent molecular pathways was achieved. This method also allowed the identification of " homophilic cell adhesion" as one of the convergent pathways of ASD-relevant genes. Analyses of CDH11 and CDH9, two specific genes coding for homophilic cell adhesion molecules, revealed that CDH11, but not CDH9, was significantly co-expressed with hcASDs. In addition, Cdh11-null mice, but not Cdh9-null mice, were found to exhibit multiple autistic-like behavioral alterations.These results suggest that CDH11 is an important ASD risk gene. Results of this study also highlight the importance of considering matched gene features in the analysis of gene coexpression.Conventionally, genome-wide gene co-expression networks are constructed after setting an empirically determined threshold of CC 6 . A major limitation in most of these studies is lack of consideration of effects of confounding factors such as the size, expression level (mRNA abundance), and guanine-cytosine (GC) content of genes on the result of gene co-expression analysis (GCA) 11 . Most hcASDs are large genes with a higher expression level in the brain than in other tissues 12 . It is unclear whether the size or expression level of genes affect the result of GCA. It is also unknown whether convergent expression is specific to ASD risk genes or a common property of genes with similar features, such as large gene size and high mRNA abundance 11 . Some hcASDs code for adhesion molecules, such as members of neurexin and neuroligin families, which mediate pre-and post-synaptic adhesion, respectively, in ASD-related brain circuits 13,14 . Genetic variants of several other adhesion molecules, including classical and nonclassical cadherin family members, are also frequently found to be associated with ASD by GWAS 15 and WES studies [16][17][18][19] . Cadherin family members play important roles in multiple developmental processes, including cell proliferation, polarization, neuronal migration, axon projection, dendrite arborization, and synapse assembly, by mediating homophilic and heterophilic cell-cell interactions [20][21][22][23][24] . It is unclear as...

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Section: Multiple Members Of the Cadherin Family As Risk Factors For Asdsupporting

confidence: 79%

Association ofCDH11with ASD revealed by matched-gene co-expression analysis and mouse behavioral studies

Wang

Jia

et al. 2020

Preprint

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“…In the past few years, advanced studies conducted using modern genetic and neuroimaging methods, such as functional magnetic resonance imaging (fMRI) have indicated that human cerebellum also sustains autonomic, limbic, and cognitive functions, including language and thinking; hence, this brain region was lately associated with the occurrence and development of autism . On the basis of the data collected by genetic testing and/or using MRI methods, other reports also relate cerebellar dysfunctions to Alzheimer disease (AD), attention‐deficit/hyperactivity disorder, Huntington disease, hereditary ataxia, and Parkinson disease (PD) .…”

Section: Introductionmentioning

confidence: 99%

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

et al. 2020

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We have developed here a superior approach based on high-resolution (HR) mass spectrometry (MS) for monitoring the changes occurring with development and aging in the composition and structure of cerebellar gangliosidome. The experiments were focused on the comparative screening and structural analysis of gangliosides expressed in fetal and aged cerebellum by Orbitrap MS with nanoelectrospray ionization (nanoESI) in the negative ion mode. The employed ultrahigh-resolution MS platform allowed the discrimination, without the need of previous separation, of 159 ions corresponding to 120 distinct species in the native ganglioside mixtures from fetal and aged cerebellar biopsies, many more than detected before, when MS platforms of lower resolution were employed. A number of gangliosides, in particular polysialylated belonging to GT, GQ, GP, and GS classes, modified by O-fucosylation, O-acetylation, or CH 3 COO − were discovered here, for the first time in human cerebellum. These components, found differently expressed in fetal and aged tissues, indicated that the ganglioside profile in cerebellum is development stage-and agespecific. Following the fragmentation analysis by high-energy collision-induced dissociation (HCD) tandem MS (MS/MS), we have also observed that the intimate structure of certain compounds has not changed during the development and aging of the brain, an aspect which could open new directions in the investigation of ganglioside biomarkers in cerebellar tissue.

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“…MiRNA322 (paired with protogenin Prtg) is associated with apoptosis and Alzheimer's disease (AD) [67]. Finally, Mir100 (paired with cadherin Cdh9), is associated with neurological disorders such as AD, schizophrenia and autism [68][69][70][71].…”

Section: Discussionmentioning

confidence: 99%

Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington’s disease mice

et al. 2020

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Background: MicroRNA (miRNA) regulation is associated with several diseases, including neurodegenerative diseases. Several approaches can be used for modeling miRNA regulation. However, their precision may be limited for analyzing multidimensional data. Here, we addressed this question by integrating shape analysis and feature selection into miRAMINT, a methodology that we used for analyzing multidimensional RNA-seq and proteomic data from a knock-in mouse model (Hdh mice) of Huntington's disease (HD), a disease caused by CAG repeat expansion in huntingtin (htt). This dataset covers 6 CAG repeat alleles and 3 age points in the striatum and cortex of Hdh mice. Results: Remarkably, compared to previous analyzes of this multidimensional dataset, the miRAMINT approach retained only 31 explanatory striatal miRNA-mRNA pairs that are precisely associated with the shape of CAG repeat dependence over time, among which 5 pairs with a strong change of target expression levels. Several of these pairs were previously associated with neuronal homeostasis or HD pathogenesis, or both. Such miRNA-mRNA pairs were not detected in cortex. Conclusions: These data suggest that miRNA regulation has a limited global role in HD while providing accuratelyselected miRNA-target pairs to study how the brain may compute molecular responses to HD over time. These data also provide a methodological framework for researchers to explore how shape analysis can enhance multidimensional data analytics in biology and disease.

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Segregated expressions of autism risk genes Cdh11 and Cdh9 in autism-relevant regions of developing cerebellum

Cited by 24 publications

References 88 publications

Association ofCDH11with ASD revealed by matched-gene co-expression analysis and mouse behavioral studies

Association ofCDH11with ASD revealed by matched-gene co-expression analysis and mouse behavioral studies

Orbitrap mass spectrometry for monitoring the ganglioside pattern in human cerebellum development and aging

Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington’s disease mice

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