Infertility-Causing Haploinsufficiency Reveals TRIM28/KAP1 Requirement in Spermatogonia

Tan, Joel Heng Loong; Wollmann, Heike; Pelt, Ans M.M. van; Kaldis, Philipp; Messerschmidt, Daniel M.

doi:10.1016/j.stemcr.2020.03.013

Cited by 19 publications

(18 citation statements)

References 38 publications

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“…For the two siblings, a different (genetic) cause of their congenital heart defect cannot be excluded, even though this was not identified with WES [15]. As mentioned previously, the male infertility observed in haploinsufficient mice [54] has not been documented in humans, but may warrant attention during the clinical follow‐up of TRIM28 mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

“…Another explanation for the maternal inheritance pattern could be that pathogenic TRIM28 variants impair spermatogenesis and result in male subfertility or infertility, as was suggested by a recent study in mice with heterozygous loss of TRIM28 [54]. This would prevent male carriers from passing the variant on to offspring.…”

Section: Biological Functions Of Trim28mentioning

confidence: 99%

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TRIM28 variants and Wilms' tumour predisposition

Hol

Diets

Krijger

et al. 2021

The Journal of Pathology

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TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases. TRIM28 variants are associated with epithelial WT, but the presence of other tumour components or anaplasia does not exclude the presence of a germline or somatic TRIM28 variant. In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour. Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants. TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context‐, species‐, and cell‐type‐specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation. In this review, we describe the inheritance patterns, histopathological and clinical features of TRIM28‐associated WT, as well as potential underlying mechanisms of tumourigenesis during embryonic kidney development. Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family. A further exploration of TRIM28‐associated WT will help to unravel the diverse and complex mechanisms underlying WT development. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Section: Biological Functions Of Trim28mentioning

confidence: 99%

TRIM28 variants and Wilms' tumour predisposition

Hol

Diets

Krijger

et al. 2021

The Journal of Pathology

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“…The absence of neutrophil in this Cas9:sgGfi1 is even more complete than the conventional Gfi1 knockout model on NOD background, which suggests the high efficiency of sgRNA targeting in the presence of Cas9 nuclease in vivo . Therefore, our experiments proved the concept to establish genetically deficient mouse models from healthy sgRNA-expressing and Cas9-expressing parental lines, which provided an alternative approach to maintain colony under challenging situations such as loss of immune protection or infertility causing haploinsufficiency ( Tan et al, 2020 ). In addition, our experiments suggested the possibility of establishing a mouse model with compound mutations as more than one sgRNA can be introduced during the knock-in process.…”

Section: Discussionmentioning

confidence: 94%

sgRNA Knock-in Mouse Provides an Alternative Approach for In Vivo Genetic Modification

Zhang

Liu

et al. 2022

Front. Cell Dev. Biol.

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Functional genomics in a mammalian model such as mice is fundamental for understanding human biology. The CRISPR/Cas9 system dramatically changed the tempo of obtaining genetic mouse models due to high efficiency. However, experimental evidence for the establishment of sgRNA knock-in animals and analyses of their value in functional genomics are still not sufficient, particularly in mammalian models. In this study, we demonstrate that the establishment of sgRNA knock-in mice is feasible, and more importantly, crosses between sgRNA knock-in mice and the Cas9 constitutively expressing mice result in complete deletion of the target gene. Such sgRNA knock-in provides an alternative approach for in vivo genetic modification and can be useful in multiple circumstances, such as maintenance of genetically modified animals, which are difficult to breed as homozygotes, and cross of such mice to diverse genomic backgrounds to obtain genetically modified animals.

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“…Images were taken by using Zeiss LSM 880 confocal microscope (Zeiss, Germany) with 63X objective. The intensity of Claudin 2 expression (corrected total cell fluorescence, CTCF) [ 25 – 27 ] was quantified in 3 images for each animal by using Fiji/ImageJ software. Co-localization coefficients M1 (fraction of claudin-2 overlapping with ZO-1) and M2 (fraction of ZO-1 overlapping with claudin-2) were obtained by using JACoP plugin in Fiji/ImageJ software.…”

Section: Methodsmentioning

confidence: 99%

In vivo and ex vivo assessment of bladder hyper-permeability and using molecular targeted magnetic resonance imaging to detect claudin-2 in a mouse model for interstitial cystitis

et al. 2020

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Objectives To determine if the URO-MCP-1 mouse model for bladder IC/BPS is associated with in vivo bladder hyper-permeability, as measured by contrast-enhanced MRI (CE-MRI), and assess whether molecular-targeted MRI (mt-MRI) can visualize in vivo claudin-2 expression as a result of bladder hyper-permeability. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, painful condition of the bladder that affects primarily women. It is known that permeability plays a substantial role in IC/BPS. Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. Claudin-2 is a molecular marker that is associated with increased hyperpermeability in the urothelium. Materials and methods CE-MRI was used to measure bladder hyper-permeability in the URO-MCP-1 mice. A claudin-2-specific mt-MRI probe was used to assess in vivo levels of claudin-2. The mt-MRI probe consists of an antibody against claudin-2 conjugated to albumin that had Gd-DTPA (gadolinium diethylenetriamine pentaacetate) and biotin attached. Verification of the presence of the mt-MRI probe was done by targeting the biotin moiety for the probe with streptavidin-horse radish peroxidase (SA-HRP). Trans-epithelial electrical resistance (TEER) was also used to assess bladder permeability. Results The URO-MCP-1 mouse model for IC/BPS was found to have a significant increase in bladder permeability, following liposaccharide (LPS) exposure, compared to saline-treated controls. mt-MRI- and histologically-detectable levels of the claudin-2 probe were found to increase with LPS -induced bladder urothelial hyper-permeability in the URO-MCP-1 IC mouse model. Levels of protein expression for claudin-2 were confirmed with immunohistochemistry and immunofluorescence imaging. Claudin-2 was also found to highly co-localize with zonula occlidens-1 (ZO-1), a tight junction protein. Conclusion The combination of CE-MRI and TEER approaches were able to demonstrate hyper-permeability, a known feature associated with some IC/BPS patients, in the LPS-exposed URO-MCP-1 mouse model. This MRI approach could be clinically translated to establish which IC/BPS patients have bladder hyper-permeability and help determine therapeutic options. In addition, the in vivo molecular-targeted imaging approach can provide invaluable information to enhance our understanding associated with bladder urothelium hyper-permeability in IC/BPS patients, and perhaps be used to assist in developing further therapeutic strategies.

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Infertility-Causing Haploinsufficiency Reveals TRIM28/KAP1 Requirement in Spermatogonia

Cited by 19 publications

References 38 publications

TRIM28 variants and Wilms' tumour predisposition

TRIM28 variants and Wilms' tumour predisposition

sgRNA Knock-in Mouse Provides an Alternative Approach for In Vivo Genetic Modification

In vivo and ex vivo assessment of bladder hyper-permeability and using molecular targeted magnetic resonance imaging to detect claudin-2 in a mouse model for interstitial cystitis

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