Methylation‐reprogrammed Wnt/β‐catenin signalling mediated prenatal hypoxia‐induced brain injury in foetal and offspring rats

Zhang, Yingying; Zhang, Mengshu; Wei, Bin; He, Axin; Lu, Likui; Li, Xiang; Zhang, Li; Xu, Zhice; Sun, Miao

doi:10.1111/jcmm.13660

Cited by 12 publications

(8 citation statements)

References 55 publications

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“…It has previously been shown that quantification of cell populations using flow cytometry correlate well with quantitative immunohistochemistry 41 . Our NGS results from the FACS isolated astrocytes indicate that the astrocytes are trying to restore the CIR-induced dysfunction ( Sfrp4, Plekha2, Nxph1 ) 25–27 and even try to convert into neurons ( Neurod1 ) 24 (Fig. 6).…”

Section: Discussionmentioning

confidence: 95%

“…In line with this, the astrocytes attempt to restore the lack of neurons as indicated by increased levels of Neurod1 , which has been shown to be able to convert astrocytes to neurons 24 . In general, genes involved in synaptic plasticity and behavior, propose that the astrocytes are trying to restore the CIR-induced dysfunction ( Sfrp4, Plekha2, Nxph1 ) 25–27 .…”

Section: Resultsmentioning

confidence: 99%

“…6). For example, Sfrp4 , known to inhibit the Wnt pathway that controls cell proliferation, differentiation and migration, was downregulated following CIR 25 . The gene expression data do however also indicate that there is an ongoing injury ( Bank1, Il1a , and Pdgfra ) 17–19 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain

Boström

Eriksson

Danial

et al. 2019

Sci Rep

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Better survival rates among pediatric brain tumor patients have resulted in an increased awareness of late side effects that commonly appear following cancer treatment. Radiation-induced changes in hippocampus and white matter are well described, but do not explain the full range of neurological late effects in childhood cancer survivors. The aim of this study was to investigate thalamus following cranial irradiation (CIR) to the developing brain. At postnatal day 14, male mice pups received a single dose of 8 Gy CIR. Cellular effects in thalamus were assessed using immunohistochemistry 4 months after CIR. Interestingly, the density of neurons decreased with 35% ( p = 0.0431) and the density of astrocytes increased with 44% ( p = 0.011). To investigate thalamic astrocytes, S100β + cells were isolated by fluorescence-activated cell sorting and genetically profiled using next-generation sequencing. The phenotypical characterization indicated a disrupted function, such as downregulated microtubules’ function, higher metabolic activity, immature phenotype and degraded ECM. The current study provides novel insight into that thalamus, just like hippocampus and white matter, is severely affected by CIR. This knowledge is of importance to understand the late effects seen in pediatric brain tumor survivors and can be used to give them the best suitable care.

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain

Boström

Eriksson

Danial

et al. 2019

Sci Rep

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“…Hypoxic conditions lead to the upregulation of WNT7a and WNT7b, mediated by the stabilization of hypoxia-inducible factor (HIF)1/2α, which resulted in decreased myelination in mouse white matter [ 52 , 91 ]. These effects were normalized by XAV939, an inhibitor of WNT/β-catenin-mediated transcription, via the stabilization of Axin [ 92 ].…”

Section: Wnt Signaling In Endothelial Cell–oligodendrocyte Crosstamentioning

confidence: 99%

A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease

Manukjan

Ahmed

Fulton

et al. 2020

Cells

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Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development.

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“…Prenatal hypoxia (PH) is fetal distress which is caused by three factors [1][2][3], including maternal factors (such as maternal nutrition, maternal smoking, and maternal hypertension), fetal factors (such as umbilical cord around neck, insufficient blood supply to the placenta and fetal asphyxia), and environment factors (such as high altitude) [1,4,5]. PH is also associated with intrauterine growth restriction, fetal brain injury, and premature delivery [6][7][8]. In addition, PH has long-term adverse health effects on offspring's health, namely, the nervous system, cardiovascular and metabolic disease, and so on [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia

Yao

et al. 2022

Reprod. Sci.

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Prenatal hypoxia (PH) is a common feature of a suboptimal intrauterine environment affecting the development of fetuses. Whether PH leads to abnormal ovary development is not yet clear. This study investigated ovarian function in offspring exposed to PH and the potential underlying molecular mechanisms. SD female rats (n = 12 per group) at 9 weeks of age were housed in individual cages (21% O2). After the pregnant rats were exposed to hypoxia (10.5% oxygen) from embryonic day (E) 5 to E21, PH offspring were generated. All animals maintained normoxia during lactation. The number of follicles was counted in female offspring at 3 months under an optical microscope. The expression of Nobox, Gdf9, and Tets was detected by quantitative real-time polymerase chain reaction (PCR) and Western blot. Global DNA hydroxymethylation was measured by dot blot. The hydroxymethylation level of the Nobox gene was evaluated with an NGS-based multiple targeted CpG hydroxymethylation analysis method. Body weight and ovary weight were significantly decreased in the PH group compared with the control group. PH offspring have abnormal estrous cycle, decreased serum anti-Mullerian hormone (AMH), and increased serum follicle-stimulating hormone (FSH), and follicular atresia, which are consistent with the clinical manifestations in patients with ovarian dysfunction. In terms of mechanism, the expression of Nobox was significantly decreased in the PH group. Subsequent high-throughput sequencing results showed that the level of hydroxymethylation in the candidate region of the Nobox gene was reduced. Cultured cells treated with hypoxia exhibited lower levels of both 5hmC and Nobox, while vitamin C, a coactivator of Tets, rescued hypo-hydroxymethylation and increased the expression level of Nobox. This study indicated that PH could cause hypo-hydroxymethylation of Nobox through epigenetic regulation and may consequently contribute to ovarian dysfunction in adult rat offspring.

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Methylation‐reprogrammed Wnt/β‐catenin signalling mediated prenatal hypoxia‐induced brain injury in foetal and offspring rats

Cited by 12 publications

References 55 publications

Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain

Chronic disturbance in the thalamus following cranial irradiation to the developing mouse brain

A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease

Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia

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