Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder

Tilot, Amanda K.; Bebek, Gürkan; Niazi, Feizollah; Altemus, Jessica; Romigh, Todd; Frazier, Thomas; Eng, Charis

doi:10.1038/mp.2015.17

Cited by 58 publications

(90 citation statements)

References 37 publications

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“…PTEN was first identified as a tumor suppressor (Li et al, 1997) but later also found to be associated with neurodevelopmental conditions such as epilepsy, macrocephaly, and autism (Goffin et al, 2001; Butler et al, 2005; Buxbaum et al, 2007; Orrico et al, 2009; Varga et al, 2009; McBride et al, 2010; Redfern et al, 2010; Stein et al, 2010; Schaaf et al, 2011; O’Roak et al, 2012b; Busa et al, 2013; De Rubeis et al, 2014; Hobert et al, 2014; Marchese et al, 2014; Vanderver et al, 2014; Codina-Sola et al, 2015; D’Gama et al, 2015; Johnston and Raines, 2015; Krumm et al, 2015; Spinelli et al, 2015; Tammimies et al, 2015; Cupolillo et al, 2016; Schwerd et al, 2016; Tilot et al, 2016). PTEN expression in the brain is positively correlated with the developmental stages of neuronal dendrite formation and synaptogenesis suggesting a role in regulating neuronal function (Perandones et al, 2004).…”

Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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“…Genes deregulated by ERt2-TEV-mediated RAD21-TEV cleavage showed significant overlap with SFARI ASD risk genes 32 (Odds ratio = 2.19, P = 1.16e-08). There was limited overlap between genes deregulated by acute cohesin depletion and other mouse models of neuronal dysfunction [33][34][35][36][37] , with the exception of gene expression in embryonic Nipbl +/brain 14 (Extended Data Fig. 6).…”

Section: Cohesin Is Continuously Required For Neuronal Gene Expressionmentioning

confidence: 99%

Partial rescue of neuronal genes deregulated in Cornelia de Lange Syndrome by cohesin

Weiss

Calderón

Wang

et al. 2020

Preprint

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Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterized the transcriptional profile of cortical neurons from CdLS patients and found deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupted 3-D genome organization and transcriptional control in post-mitotic cortical mouse neurons. The genes affected belonged to similar gene ontology classes and showed significant numerical overlap with those deregulated in CdLS. Interestingly, gene expression was largely rescued by subsequent reconstitution of cohesin function. These experiments show that cohesin is continuously required for neuronal gene expression and provide a tractable approach for addressing mechanisms of neuronal dysfunction in CdLS.

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“…We compared DEGs from Tcf4 +/mut mice with two mouse models of ASD, MeCP2 knockout (Mecp2 KO ) (18) and homozygous Pten mutation (Pten m3m4/m3/m4 ) (16). We processed the Mecp2 KO and Pten m3m4/m3/m4 RNA-seq datasets as described below and compared genes differentially expressed in our pooled TCF4 analysis to those also differentially expressed in MeCP2 and Pten homozygous mutations (FDR<0.05).…”

Section: Comparing Transcriptomes Of Multiple Syndromic Asd Mouse Modelsmentioning

confidence: 99%

“…Together, these data suggest that TCF4 is critical to the proper maturation of oligodendrocytes and the process of myelination but not in the development of oligodendrocyte precursor cells.Syndromic forms of ASD are caused by varying mutations yet share significant overlap in their symptomology, suggesting that common biological processes underlie many forms of ASD. We therefore compared DEGs in adult Tcf4 +/mut mouse brains to mouse models of PTEN-associated autism (Pten m3m4/m3m4 ; (15,16)) and Rett syndrome (Mecp2 KO ; (17) , (18)) to characterize shared 6 gene regulation between these three mouse models of syndromic ASD. Remarkably, we found significant overlap of DEGs in Tcf4 +/mut vs. Pten m3m4/m3m4 and Tcf4 +/mut vs. Mecp2 KO mutations ( Fig.…”

mentioning

confidence: 99%

“…Syndromic forms of ASD are caused by varying mutations yet share significant overlap in their symptomology, suggesting that common biological processes underlie many forms of ASD. We therefore compared DEGs in adult Tcf4 +/mut mouse brains to mouse models of PTEN-associated autism (Pten m3m4/m3m4 ; (15,16)) and Rett syndrome (Mecp2 KO ; (17) , (18)) to characterize shared gene regulation between these three mouse models of syndromic ASD. Remarkably, we found significant overlap of DEGs in Tcf4 +/mut vs. Pten m3m4/m3m4 and Tcf4 +/mut vs. Mecp2 KO mutations ( and Pten mutations may arise from regulation of common downstream targets such as Akt2 or Mtor, two DEGs in our dataset that participate in the Akt-PTEN-mTOR pathway (21).…”

mentioning

confidence: 99%

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Defects of myelination are common pathophysiology in syndromic and idiopathic autism spectrum disorder

Phan

Page

Campbell

et al. 2017

Preprint

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Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Pten m3m4/m3m4 , Mecp2 KO ). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.Main Text: Autism spectrum disorder (ASD) affects approximately 1:68 individuals and has incalculable burdens on affected individuals, their families, and health care systems. While the genetic contributions to idiopathic ASD are heterogeneous and largely unknown, the causal mutations for syndromic forms of ASD -including truncations and copy number variantsprovide a genetic toehold with which to gain mechanistic insights(1-3). Models of these syndromic disorders have been used to better characterize the molecular and physiological processes disrupted by these mutations(4). Two fundamental questions remain -how . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/128124 doi: bioRxiv preprint first posted online Apr. 18, 2017; 3 biologically similar are the mouse models of syndromic forms of ASD, and how relevant are these mouse models to their human analogs? To address these questions, we performed integrative transcriptomic analyses of seven independent mouse models of three syndromic forms of ASD generated across five laboratories, and assessed dysregulated genes and their pathways in human postmortem brain from patients with ASD and unaffected controls. These cross-species analyses converged on shared disruptions in myelination and axon development across both syndromic and idiopathic ASD, highlighting both the face validity of mouse models for these disorders and identifying novel convergent molecular phenotypes amendable to rescue with therapeutics.We first assessed molecular convergence across five different mouse models of Pitt-Hopkins syndrome (PTHS), a rare form of ASD that results from diverse mutations in the transcription factor 4 (TCF4) gene, ranging from haploinsufficiency to dominant-negative. This syndromic disorder is cha...

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Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder

Cited by 58 publications

References 37 publications

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Partial rescue of neuronal genes deregulated in Cornelia de Lange Syndrome by cohesin

Defects of myelination are common pathophysiology in syndromic and idiopathic autism spectrum disorder

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