A Portal to Visualize Transcriptome Profiles in Mouse Models of Neurological Disorders

Al‐Ouran, Rami; Wan, Ying-Wooi; Mangleburg, Carl Grant; Lee, Tom V.; Allison, Katherine S.; Liu, Zhandong

doi:10.3390/genes10100759

Cited by 10 publications

(6 citation statements)

References 13 publications

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“…The nonTG littermates of these mice showed no correlation between Abi3 and Gngt2 expression. In addition, we investigated 96 additional mouse transcriptomic datasets [ 33 , 34 ] and in 26 of these cohorts, we found that Abi3 and Gngt2 were both differentially regulated. Among these 26 cohorts, Abi3 and Gngt2 expression changes were concordant in 24 studies (Additional File 6 : Table S4), showing that these genes are consistently co-regulated across different mouse models and experimental cohorts.…”

Section: Resultsmentioning

confidence: 99%

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

et al. 2022

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Background The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer’s disease (AD), but little is known about its function in relation to AD pathogenesis. Methods Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD—amyloid β plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies. Results Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3−/− mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2−/− mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3-Gngt2−/− mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. Conclusions These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.

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Section: Resultsmentioning

confidence: 99%

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

et al. 2022

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“…5J-K ). We first used a mouse RNA-seq portal that includes mouse transcriptomic datasets related to multiple neurological disorders and aging models ( 39 ). Interestingly, many of the genes with differential E-P interactions across the estrous cycle, while not showing gene expression changes in our physiological mouse model, exhibit aberrant expression in mouse models of neurological diseases ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Gene ontology and pathway analyses were performed by EnrichR ( 64 ) and the Ingenuity Pathway Analysis (IPA) software (https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis). Comparison of expression in other tissues was done using the Human Protein Atlas database ( 31 ) and for disease models using the Mouse neurological disorders RNA-seq portal ( 39 ).…”

Section: Methodsmentioning

confidence: 99%

Sex-specific multi-level 3D genome dynamics in the mouse brain

Rocks

Shukla

Finnemann

et al. 2021

Preprint

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The female mammalian brain exhibits sex-hormone-driven plasticity during the reproductive period. Evidence implicates chromatin dynamics in gene regulation underlying this plasticity. However, whether ovarian hormones impact higher-order chromatin organization in post-mitotic neurons in vivo is unknown. Here, we mapped 3D genome of ventral hippocampal neurons across the estrous cycle and by sex in mice. In females, we found cycle-driven dynamism in 3D chromatin organization, including in estrogen-response-elements-enriched X-chromosome compartments, autosomal CTCF loops, and enhancer-promoter interactions. With rising estrogen levels, the female 3D genome becomes more similar to the male genome. Cyclical enhancer-promoter interactions are partially associated with gene expression and enriched for brain disorder-relevant genes. Our study reveals unique 3D genome dynamics in the female brain relevant to female-specific gene regulation, neuroplasticity, and disease risk.

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“…The NonTG littermates of these mice showed no correlation between Abi3 and Gngt2 expression. In addition, we investigated 96 additional mouse transcriptomic datasets (Al-Ouran et al, 2019, Wan et al, 2020 and in 26 cohorts, we found that Abi3 and Gngt2 were both differentially regulated. Among these 26 of these cohorts, Abi3 and Gngt2 expression changes were concordant in 24 studies (Table EV3), showing that these genes are consistently co-regulated across different mouse models and experimental cohorts.…”

Section: Abi3 and Gngt2 Genes Are Co-regulated In App Mouse Models And In Admentioning

confidence: 99%

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

Ibanez

McFarland

Phillips

et al. 2021

Preprint

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The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer’s disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

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A Portal to Visualize Transcriptome Profiles in Mouse Models of Neurological Disorders

Cited by 10 publications

References 13 publications

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

Sex-specific multi-level 3D genome dynamics in the mouse brain

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

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