Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis

Goodwin, Leslie O.; Splinter, Erik; Davis, Tiffany L.; Urban, Rachel; He, Hao; Braun, Robert E.; Chesler, Elissa J.; Kumar, Vivek; Min, Max van; Ndukum, Juliet; Philip, Vivek; Reinholdt, Laura G.; Svenson, Karen L.; White, Jacqueline K.; Sasner, Michael; Lutz, Cathleen

doi:10.1101/236307

Cited by 56 publications

(70 citation statements)

References 38 publications

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“…Founders were identified and mated to wild-type C57BL/6NTac females. Analysis of integration site indicates insertion occurred at Chr11:40456787-40495044 and resulted in a 38.4 Kb deletion 69 . Copy number analysis was also performed on tail clips of the mice using the following primers and probe combination (spanning exons 2 and 3 of hSNCA gene):…”

Section: Methodsmentioning

confidence: 99%

Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

et al. 2020

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Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy.

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Section: Methodsmentioning

confidence: 99%

Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

et al. 2020

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“…The DNA also usually concatemerizes so the animal has multiple copies of the transgene and thus overexpresses the protein of interest. A study of 40 well-cited transgenic strains, many of which are used in neurodegeneration research, showed that about half had mutations at the insertion site, although little phenotypic outcome appears to be associated with these insertional mutation events (51). Injected constructs are often cDNAs under the control of non-endogenous promotors that are not expressed with the same pattern as the endogenous gene and are only expressed as the splice isoform encoded by the cDNA.…”

Section: Mouse Modeling: What Is the Question?mentioning

confidence: 99%

Mouse models of neurodegeneration: Know your question, know your mouse

Fisher

Bannerman

2019

Sci. Transl. Med.

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Overline: Neurodegenerative Disease Single Sentence Summary:We can now create an unprecedented set of mouse models for understanding neurodegeneration and we need to carefully consider which model best fits our research question and how to learn from the variability within and between studies. AbstractMany mutant mouse strains have been developed to investigate neurodegenerative diseases, but variability among mouse studies has led to questioning of the value of these mouse models. Here, we appraise various mouse models for dissecting neurodegenerative mechanisms and emphasise the importance of asking appropriate scientific questions and understanding variability among and within studies. In therapeutics research, we suggest that not embracing this variability in mouse models may contribute to translational failure in human patients.

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“…Among these, there was a significant (exact binomial test, n = 154 transcripts, P = 0.00014) enrichment of downregulated transcripts (n = 101 (66%) transcripts with reduced expression in TG compared to n = 53 (34%) transcripts with elevated expression in TG). Of note, differences for five of these transcripts are likely to reflect known deletions of the transgene integration sites for the CaMKIIα-tTA (encompassing Wdr60, Esyt2, Ncapg2, and Ptprn2) and MAPT (encompassing Fgf14) transgenes 30 . Given the high homology between transcribed regions of the human and mouse tau gene, we also find highly elevated levels of Mapt (Wald statistic = 11.11, log2 fold change = 0.50, FDR = 7.08E-25) (Supplementary Figure 5a) confirming stable activation of the MAPT transgene in TG mice; of note, human-specific MAPT sequence domains were only detected in TG RNA-seq datasets (Supplementary Figure 5b-c).…”

Section: The Rtg4510 Model Of Tau Pathology Is Characterized By Widesmentioning

confidence: 99%

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models

Castanho

Hannon

et al. 2019

Preprint

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The onset and progression of Alzheimer's disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and accumulation of β-amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. Differentially expressed transcripts included genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in GWAS and exome-sequencing studies of late-onset sporadic AD. Systemslevel analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report considerable overlap between tau-associated networks and AD-associated co-expression modules identified in the human cortex. Our data provide further support for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.3

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Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis

Cited by 56 publications

References 38 publications

Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

Mouse models of neurodegeneration: Know your question, know your mouse

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models

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