scholarly journals The impact of phosphorylated Pten at threonine 366 on cortical connectivity and behaviour

2021 ◽  
Author(s):  
Julia Ledderose ◽  
Jorge A Benitez ◽  
Amanda J Roberts ◽  
Rachel Reed ◽  
Willem Bintig ◽  
...  
Keyword(s):  
Sensory Processing ◽  
Cortical Neurons ◽  
Suppressor Gene ◽  
Autism Spectrum ◽  
Tumour Suppressor Gene ◽  
Repetitive Behaviour ◽  
Cortical Input ◽  
Brain Circuits ◽  
Neuron Size ◽  
The Impact

The lipid phosphatase Pten (phosphatase and tensin homologue on chromosome 10) is a key tumour suppressor gene and an important regulator of neuronal signalling. Pten mutations have been identified in patients with autism spectrum disorders, characterized by macrocephaly, impaired social interactions and communication, repetitive behaviour, intellectual disability, and epilepsy. Pten enzymatic activity is regulated by a cluster of phosphorylation sites at the C-terminus of the protein. Here we specifically focussed on the role of Pten T366 phosphorylation and generated a knock-in mouse line in which Pten T366 was substituted with alanine (PtenT366A/T366A). We identify that phosphorylation of Pten at T366 controls neuron size and connectivity of brain circuits involved in sensory processing. We show in behavioural tests that PtenT366/T366A mice exhibit cognitive deficits and selective sensory impairments, with significant differences in male individuals. We identify restricted cellular overgrowth of cortical neurons in PtenT366A/T366A brains, linked to increases in both dendritic arborization and soma size. In a combinatorial approach of anterograde and retrograde monosynaptic tracing using rabies virus, we characterize differences in connectivity to the primary somatosensory cortex of PtenT366A/T366A brains, with imbalances in long-range cortico-cortical input to neurons. We conclude that phosphorylation of Pten at T366 controls neuron size and connectivity of brain circuits involved in sensory processing and propose that PTEN T366 signalling may account for a subset of autism-related functions of Pten.

scholarly journals A Pilot Study Comparison of Sensory Integration Treatment and Integrated Preschool Activities for Children with Autism

2012 ◽  
Author(s):  
Sandra Dunbar ◽  
Jennifer Carr-Hertel ◽  
Helene Lieberman ◽  
Belinda Perez ◽  
Kristi Ricks
Keyword(s):  
Pilot Study ◽  
Small Groups ◽  
Sensory Processing ◽  
Sensory Integration ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Post Test ◽  
Spectrum Disorders ◽  
Outcome Differences ◽  
The Impact

This exploratory pilot study was conducted to evaluate outcome differences between traditional individualized sensory integration treatment and integrated sensorimotor activities for preschool children with autism spectrum disorders. Pre- and post test measures of play were evaluated for two small groups of children who met criteria for exhibiting sensory processing issues. Results indicated positive differences in play behavior for both groups of children. Overall, further research is indicated to better understand the impact of various treatment approaches on participation in preschool occupations.

scholarly journals The Impact of gain1q on Mutational Structure and Clonal Evolution in a Uniformly Treated High-Risk Series of Patients at First Relapse

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2683-2683
Author(s):  
John R Jones ◽  
Charlotte Pawlyn ◽  
Niels Weinhold ◽  
Timothy Cody Ashby ◽  
Brian A Walker ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Mutational Load ◽  
Advisory Committees ◽  
The Impact ◽  
Support Research

Abstract Introduction In Multiple Myeloma (MM) the emergence of treatment resistant clones is a characteristic feature of relapse and this is particularly so for high-risk cases. A key driver event mediating progression, risk status and relapse is gain(1q) (1q+). We report on the impact of 1q+ on the genetic profile seen at first relapse in a uniformly treated, newly diagnosed series of 56 patients enrolled to the NCRI Myeloma XI Trial. Methods We included 56 high risk patients, defined as relapse within 30 months of maintenance randomisation (median 19 months, range 8-51). Of the 56 patients, 30 received lenalidomide maintenance and 26 were observed. Whole exome sequencing was conducted at presentation and relapse to a median depth of 122x for tumour samples and 58x for controls. Libraries were prepared using the SureSelectQXT sample prep kit and SureSelect Clinical Research Exome kit. MuTect was used to determine gene variants and SciClone clustering was undertaken to map mutation variant allele frequencies. MANTA was used to determine translocations and Sequenza for copy number aberrations. Clonal structure and mechanisms of clonal evolution were assessed using kernel density estimation of the cancer clonal fraction for all mutations. Wilcoxon matched-pairs signed rank tests (2-sided) were used to determine the significance between paired data sets, including mutational load. Fishers exact test was used to determine the difference between two nominal variables. Results We looked at mutational, structural and clonal evolution events in all patients based on 1q+ status at relapse. At diagnosis, 34% (19/56) patients had evidence of 1q+, increasing to 46% (26/56) at relapse, with all patients harbouring 1q+ at presentation having the lesion at relapse. There was a significantly higher non-synonymous mutational load at relapse in patients with 1q+, 107 vs 126 (p=0.047), compared to those without 1q+, 36 vs 44 (p=0.140). Twenty two genes known to be significant in MM and mutations within the genes known to be important in IMiD mechanism of action were reviewed. Of the patients with 1q+, 92% (24/26) had at least one mutation during the course of the disease, compared to 77% in those without 1q+ (p=0.15). The impact on tumour suppressor gene regions including deletions of chromosome 1p, 13, 14 and 17p was analyzed. Of the patients with 1q+, 77% (20/26) of patients had a deletion of one of these regions during the disease course, compared to 57% (17/30) of patients without 1q+ (p=0.16). At relapse a change in the profile of these lesions was noted in 23% (6/26) patients with 1q+, compared to 20% (6/30) patients without 1q+ (p=1). Translocations involving MYC (t MYC) were also determined and found in 27% (7/26) of patients with 1q+ and 27% (8/30) of patients without (p=1). As with 1q+, t MYC was always preserved at relapse. Mechanisms of evolution leading to relapse were established for all patients. Branching and linear evolution predominated, noted to be the mechanism leading to relapse in 88% (23/26) patients with 1q+ and 83% (25/30) without (p0.71). Stable evolution was noted in the remaining patients. 1q+ occurring as a new event at relapse was associated with branching or linear evolution in all patients (n=7), consistent with a change in clonal structure. Conclusion These data reveal that 1q+ is conserved throughout the disease course, suggesting it imparts a survival advantage and treatment resistant phenotype to the clone(s) containing it. The presence of 1q+ is associated with a significant increase in mutational load at relapse and a greater incidence of tumour suppressor gene structural deletions, mechanisms that may contribute to clonal evolution and therapeutic escape. Disclosures Jones: BMS/Celgene: Other: Conference fees; Janssen: Honoraria. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weinhold: Sanofi: Honoraria. Walker: Sanofi: Speakers Bureau; Bristol Myers Squibb: Research Funding. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Kaiser: AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Amgen: Honoraria; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Takeda: Consultancy, Other: Educational support. Cook: Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jackson: oncopeptides: Consultancy; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Davies: BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

2021 ◽  
Author(s):  
Ines Serra ◽  
Ana Stravs ◽  
Catarina Osorio ◽  
Maria Roa Oyaga ◽  
Martijn Schonewille ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Suppressor Gene ◽  
Inhibitory Interneuron ◽  
Autism Spectrum ◽  
Tumour Suppressor Gene ◽  
Mtor Pathway ◽  
Cerebellar Development ◽  
Mrna Levels ◽  
Gene And Protein Expression ◽  
And Migration

Tuberous sclerosis complex 1 (TSC1) is a tumour suppressor gene that inhibits the mechanistic target of rapamycin (mTOR) pathway. Mutations in TSC1 lead to a rare complex disorder of the same name, in which up to 50% of patients present with autism spectrum disorder (ASD). ASD is a highly prevalent, early-onset neurodevelopmental disorder, characterized by social deficits and repetitive behaviours, although the type and severity of symptoms show wide variability across individuals. Amongst different brain areas proposed to play a role in the development of ASD, the cerebellum is commonly reported to be altered, and cerebellar-specific deletion of Tsc1 in mice is sufficient to induce an ASD-like phenotype. Given that the mTOR pathway is crucial for proper cell replication and migration, this suggests that dysregulation of this pathway, particularly during critical phases of cerebellar development, could contribute to the establishment of ASD. Here, we used a mouse model of TSC to investigate gene and protein expression during embryonic and early postnatal periods of cerebellar development. We found that, at E18 and P7, mRNA levels of the cerebellar inhibitory interneuron marker Pax2 were dysregulated. This was accompanied by changes in the expression of mTOR pathway-related genes and downstream phosphorylation of S6. Differential gene correlation analysis revealed dynamic changes in correlated gene pairs across development, with an overall loss of correlation between mTOR- and cerebellar-related genes in Tsc1 mutants compared to controls. We corroborated the genetic findings by characterizing the mTOR pathway and cerebellar development on protein and cellular levels with Western blot and immunohistochemistry. We found that Pax2-expressing cells were hypertrophic at E18 while, at P7, their number was increased and maturation into parvalbumin-expressing cells delayed. Our findings indicate that E18 and P7 are crucial time points in cerebellar development in mice that are particularly susceptible to mTOR pathway dysregulation.

scholarly journals Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

2019 ◽  
Author(s):  
Monica Frega ◽  
Katrin Linda ◽  
Jason M. Keller ◽  
Güvem Gümüş-Akay ◽  
Britt Mossink ◽  
...  
Keyword(s):  
Neural Network ◽  
Neuronal Network ◽  
Cortical Neurons ◽  
Critical Role ◽  
Ips Cells ◽  
Autism Spectrum ◽  
Human Model ◽  
Human Neurons ◽  
Kleefstra Syndrome ◽  
The Impact

AbstractEpigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects. Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.

scholarly journals Implications of Sensory Processing and Attentional Differences Associated With Autism in Academic Settings: An Integrative Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Courtney Mallory ◽  
Brandon Keehn
Keyword(s):  
Academic Performance ◽  
Student Success ◽  
Sensory Processing ◽  
Academic Outcomes ◽  
Autism Spectrum ◽  
Educational Material ◽  
Intellectual Ability ◽  
Classroom Environments ◽  
Academic Settings ◽  
The Impact

The impact of classroom environments on student engagement and academic performance is well-documented. Autism spectrum disorder (ASD) is associated with atypical sensory processing and attentional impairments, which may lead to challenges in successfully accessing educational material within these settings. These symptoms may help explain why students with ASD show discrepancies between intellectual ability and academic performance. Given the increasing number of students with ASD present in classrooms, understanding strengths and weaknesses in sensory processing and attention is necessary in order to design better classroom environments and develop more efficacious accommodations and interventions to support optimal student success. Therefore, the objectives of this review are to provide a brief review of the current literature on sensory processing and attention in ASD, survey how sensory and attentional functions affect academic outcomes in both neurotypical and ASD learners, and suggest potential accommodations/interventions for students with ASD based on these findings.

scholarly journals Cis-regulatory Element Hijacking Overshadows Topological Changes in Prostate Cancer

2021 ◽  
Author(s):  
James R. Hawley ◽  
Stanley Zhou ◽  
Christopher Arlidge ◽  
Giacomo Grillo ◽  
Ken Kron ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Large Scale ◽  
Genome Instability ◽  
Regulatory Element ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Structural Variants ◽  
The Impact ◽  
Topological Changes

AbstractProstate cancer is a heterogeneous disease whose progression is linked to genome instability 1. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions 2. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking 2,3 that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

scholarly journals CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 3832 ◽  
Author(s):  
Charles Bailey ◽  
Cynthia Metierre ◽  
Yue Feng ◽  
Kinsha Baidya ◽  
Galina Filippova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Somatic Cells ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Absolute Requirement ◽  
The Impact

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing as well as examined the growth and development of heterozygous Ctcf (Ctcf+/−) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf+/− MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression, and decreased survival after apoptotic insult compared to wild-type MEFs. CRISPR/Cas9-mediated targeting in Ctcf+/− MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.

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