Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation

Niu, Jianqin; Yu, Guangdan; Wang, Xiaorui; Xia, Wenlong; Wang, Yuxin; Hoi, Kimberly K.; Mei, Feng; Xiao, Lan; Chan, Jonah R.; Fancy, Stephen P.J.

doi:10.1016/j.neuron.2021.07.018

Cited by 32 publications

(34 citation statements)

References 41 publications

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“…We further con rmed the hyperactivation of Wnt/β-catenin pathway in the OPCs, from the hippocampus of schizophrenia patients, by detecting an increased immunoreactivity of Wnt downstream gene RNF43 (181.4 ± 30.5% increase, Figure 6G-H). This is consistent with a recent nding that upregulation of RNF43 speci cally in OPCs correlates with hyperactivated Wnt-signaling in injuries 32,33 . In this regard, we postulate that the DISC1-Δ3 in OPCs mediates a 'gain-of-function' to promote the hyperactivity of the Wnt/β-catenin signaling pathway in schizophrenia brains.…”

Section: Hyperactivity Of Wnt/β-catenin Pathway In Opcs From Schizoph...supporting

confidence: 93%

“…Our study further corroborates the multi-functional role of OPCs in the central nervous system (CNS). In other neurological disorders, such as multiple sclerosis, hypoxic-ischemic encephalopathy, and psychiatric diseases, OPCs not only contribute to aberrant myelin formation 33,51 , but are also involved in the regulation of blood-brain barrier integrity 36 , CNS immune regulation 53,54 and the behavioral outcomes 55,56 . In the present study, we generated a novel transgenic mouse strain to model the heterozygous DISC1 exon 3 splicing in patients with schizophrenia, and provided new evidence that such manipulation of DISC1 gene transcription exclusively in OPCs causes OPC hypertrophy, disrupts the formation of vGLUT1 + excitatory synapses, and initiate schizophrenia-like symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

Niu

et al. 2022

Preprint

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Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs’ Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1) leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.

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Section: Hyperactivity Of Wnt/β-catenin Pathway In Opcs From Schizoph...supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

Niu

et al. 2022

Preprint

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“…The g-ratio, given by the ratio of axon diameter to the summed diameter of axon and its surrounding myelin sheath, is an indicator of the degree of myelination in myelinated axons. A smaller g-ratio indicates a higher degree of myelination ( Buckley, et al 2010 ; Niu, et al 2021 ). A plot of g-ratios against axon diameters revealed that axons with larger diameters possessed significantly thicker myelination (i.e., smaller g-ratios) in the CC region of surface fish compared with cavefish ( fig.…”

Section: Resultsmentioning

confidence: 99%

Quantitative Lipidomics and Spatial MS-Imaging Uncovered Neurological and Systemic Lipid Metabolic Pathways Underlying Troglomorphic Adaptations in Cave-Dwelling Fish

Lam

Sun

et al. 2022

Molecular Biology and Evolution

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The Sinocyclocheilus represents a rare, freshwater teleost genus endemic to China that comprises the river-dwelling surface fish and the cave-dwelling cavefish. Using a combinatorial approach of quantitative lipidomics and mass-spectrometry imaging (MSI), we demonstrated that neural compartmentalization of lipid distribution and lipid metabolism are associated with the evolution of troglomorphic traits in Sinocyclocheilus. Attenuated DHA biosynthesis via the Δ4 desaturase pathway led to reductions in docosahexaenoic acid (DHA)-phospholipids in cavefish cerebellum. Instead, cavefish accumulates arachidonic acid (ARA)-phospholipids that may disfavor retinotectal arbor growth. Importantly, MSI of sulfatides, coupled with immunostaining of myelin basic protein and transmission electron microscopy images of hindbrain axons revealed demyelination in cavefish raphe serotonergic neurons. Demyelination in cavefish parallels the loss of neuroplasticity governing social behavior such as aggressive dominance. Outside the brain, quantitative lipidomics and qRT-PCR revealed systemic reductions in membrane esterified DHAs in the liver, attributed to suppression of genes along the Sprecher pathway (elovl2, elovl5, acox1). Development of fatty livers was observed in cavefish, likely mediated by an impeded mobilization of storage lipids, as evident in the diminished expressions of pnpla2, lipea, lipeb, dagla and mgll; and suppressed β-oxidation of fatty acyls via both mitochondria and peroxisomes, reflected in the reduced expressions of cpt1ab, hadhaa, cpt2, decr1 and acox1. These neurological and systemic metabolic adaptations serve to reduce energy expenditure, forming the basis of recessive evolution that eliminates non-essential morphological and behavioral traits, giving cavefish a selective advantage to thrive in caves where proper resource allocation becomes a major determinant of survival.

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“…All human HIE tissue was collected with informed consent and in accordance with guidelines established by UCSF Committee on Human Research (H11170-19113-07) as previously described 111 . Immediately after procurement, all brains were immersed in PBS with 4% paraformaldehyde for 3 d. On day 3, the brain was cut in the coronal plane at the level of the mammillary body and immersed in fresh 4% paraformaldehyde and PBS for an additional 3 d. After fixation, all tissue samples were equilibrated in PBS with 30% sucrose for at least 2 d. After sucrose equilibration, tissue was placed into molds and embedded with optimal cutting temperature medium for 30 min at room temperature followed by freezing in dry ice–chilled ethanol.…”

Section: Methodsmentioning

confidence: 99%

CRISPRi screens in human astrocytes elucidate regulators of distinct inflammatory reactive states

Leng

Rose²,

Kim

et al. 2021

Preprint

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In response to central nervous system injury or disease, astrocytes become reactive, adopting context-dependent states with altered functions. Certain inflammatory insults induce reactive astrocyte states that lose homeostatic functions and gain harmful outputs, and likely contribute to neuroinflammatory and neurodegenerative diseases. However, the cellular pathways controlling these states are not fully understood. Here, we combined single-cell transcriptomics with CRISPRi screening in human iPSC-derived astrocytes to systematically interrogate inflammatory reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-kappaB activation drove two distinct inflammatory reactive states promoted by and inhibited by STAT3, respectively. Furthermore, these states corresponded with those observed in other experimental contexts, including in vivo, and their markers were upregulated in the human brain in Alzheimer's disease and hypoxic ischemic encephalopathy. These results and the platform we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

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Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation

Cited by 32 publications

References 41 publications

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

Quantitative Lipidomics and Spatial MS-Imaging Uncovered Neurological and Systemic Lipid Metabolic Pathways Underlying Troglomorphic Adaptations in Cave-Dwelling Fish

CRISPRi screens in human astrocytes elucidate regulators of distinct inflammatory reactive states

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