Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility

Silva, Ana Isabel; Haddon, Josephine E.; Syed, Yasir Ahmed; Trent, Simon; Lin, Tzu-Ching Esther; Patel, Yatish; Carter, Jennifer; Haan, Niels; Honey, Robert Colin; Humby, Trevor; Assaf, Yaniv; Owen, Michael John; Linden, David; Hall, Jérémy; Wilkinson, Lawrence S.

doi:10.1038/s41467-019-11119-7

Cited by 64 publications

(67 citation statements)

References 74 publications

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“…We also found brain sizes comparable in both WTs and crmp2 −/− mice, similar as reported in the CRMP2 knockout mice , although we detected a non‐significant tendency for a thinner cortex in the knockout mice (not shown) in agreement with the hypoplastic corpus callosum and anterior commissure. Changes in interhemispheric connectivity have recently been linked to ASD and schizophrenia through CYFIP1, a CRMP2 binding partner . Importantly, we demonstrate that CRMP2 knockout leads to defects in axonal pruning and dendritic spine remodeling compatible with ASD rather than schizophrenia (Figs , and ).…”

Section: Discussionmentioning

confidence: 51%

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

et al. 2020

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Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2−/− mice we demonstrate that CRMP2 has a moderate effect on Sema3A‐dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2−/− mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2−/− mice display ASD‐related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F‐dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

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Section: Discussionmentioning

confidence: 51%

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

et al. 2020

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“…No effects of the treatment have been detected on either proliferation or cell viability ( Figure S3). Importantly, the morphological characterization of cells revealed that the increased number of MBP + cells found after MTK treatment in SOD1 G93A cultures could be ascribed to cells displaying a bushy morphology, typical of cells capable of producing myelin sheaths [41], and not to cells with a ring-like structure, which is instead indicative of still immature phenotype (Figure 6C,D). Globally, these results unveil the existence of intrinsic differentiation defects in SOD1 G93A OPCs and highlight the GPR17 blockade by its antagonist MTK as an effective approach to correct this dysfunction.…”

Section: Restoration Of the Differentiation Capabilities Of Opcs Frommentioning

confidence: 99%

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

Bonfanti

Bonifacino

Raffaele

et al. 2020

IJMS

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management.

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“…Most in vivo studies of Cyfip1 have relied on heterozygous models, where Cyfip1 expression is altered in all cells, making inferring cell autonomy of phenotypes extremely challenging (Bozdagi et al, 2012;Pathania et al, 2014;De Rubeis et al, 2013). This is highlighted by two recent studies on rodent Cyfip1 haploinsufficient models that both reported myelin thinning, but drew different conclusions as to whether altered neuronal activity or oligodendrocyte function underpinned these effects (Domínguez-Iturza et al, 2019;Silva et al, 2019). Indeed, microglia are in active and intimate association with neurons during key stages in development, which helps to shape neuronal connectivity (Miyamoto et al, 2016;Schafer et al, 2012;Squarzoni et al, 2014;Wake et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1

Drew

Arancibia-Cárcamo

Jolivet

et al. 2020

Preprint

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Microglia use a highly complex and dynamic network of processes to sense and respond to their surroundings. Microglial dynamics differ throughout development and in neurological and neuropsychiatric disease, though mechanistic insight into these changes is lacking. Here we identify novel roles for regulators of the actin cytoskeleton in controlling microglial behaviour. We show that the actin branching complex Arp2/3 is critical for maintaining microglial morphology and required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated Cyfip1, a core

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Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility

Cited by 64 publications

References 74 publications

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1

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