Loss of CRMP1 and CRMP2 results in migration defects of Purkinje cells in the X lobule of the mouse cerebellum

Akinaga, Satoshi; Harada, Sayaka; Takahashi, Miyuki; Kaneko, Aosa; Kolattukudy, P.E.; Goshima, Yoshio; Ohshima, Toshio

doi:10.1016/j.brainres.2022.147846

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…It is most well-known as a microtubule-stabilizing protein that functions by forming tetramers with itself or other CRMPs that stabilize assembled microtubules and traffic tubulin dimers to their plus end 4 . Consequently, CRMP2 is a mitigator of diverse cytoskeletal-related functions including mitosis, cell migration 5; 6 , endocytosis, mitochondrial morphology and motility 7 , kinesin and dynein-facilitated molecular transport, cell polarity, and dendritic and axonal elongation 2; 8; 9 . Additionally, CRMP2 acts as a modulator of calcium homeostasis and neurotransmitter release by both regulating the trafficking of calcium channel subunits and binding to NMDAR receptors to inhibit their activity 2; 10; 11 .…”

Section: Introductionmentioning

confidence: 99%

“…Genetic variants in DPYSL2 have been associated with schizophrenia (SCZ) 14; 18; 19 , bipolar disorder (BPD) 18 , Alzheimer’s disease (AD) 20 , autism spectrum disorder (ASD) 21; 22 , and intellectual disability 23 . Mouse DPYSL2 knockout models recapitulate SCZ and ASD-associated pathologies including behavioral abnormalities, gross structural changes in brain, neuron morphological abnormalities, deficits in synaptic pruning, and perturbation of glutamatergic signaling 2; 5; 8; 24; 25 . Reduced CRMP2 abundance has been observed in postmortem brain samples of patients with SCZ, BPD, major depressive disorder (MDD) 26 , and Down’s syndrome 27 .…”

Section: Introductionmentioning

confidence: 99%

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DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Feuer

Peng

Yovo

et al. 2022

Preprint

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DPYSL2/CRMP2 is a microtubule-stabilizing protein crucial for neurogenesis and associated with numerous psychiatric and neurodegenerative disorders. DPYSL2 has multiple RNA and protein isoforms, but few studies have differentiated between them or explored their individual functions. We previously demonstrated in HEK293 cells that a schizophrenia-associated variant in the DPYSL2 B isoform (DPYSL2-B) reduced the length of cellular projections, created a transcriptomic disturbance that captured schizophrenia etiology, and was acted upon by the mTOR pathway. In the present study, we follow up on these results by creating, to our knowledge, the first models of endogenous DPYSL2-B knockout in human induced pluripotent stem cells and excitatory glutamatergic neurons. We use CRISPR/Cas9 to specifically knock out DPYSL2-B and observe corresponding reduction of its RNA and protein. The average length of dendrites in knockout neurons was reduced up to 58% compared to controls. Transcriptome analysis reveals disruptions in pathways highly relevant to psychiatric disease including mTOR signaling, cytoskeletal dynamics, immune function, calcium signaling, and cholesterol biosynthesis. We also observed a significant enrichment of our differentially expressed genes in schizophrenia GWAS-associated loci. Our findings clarify the functions of the human DPYSL2-B isoform and confirm its involvement in molecular pathologies shared between many psychiatric diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Feuer

Peng

Yovo

et al. 2022

Preprint

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“…In addition, we observed the downregulation of Cdk5, Crmp1, and Crmp2 at weaning following maternal GBH exposure. Because these gene products have been suggested to contribute to the migration and alignment of Purkinje cells, 50,56 GBH might have also stimulated the irregular alignment of Purkinje cells at weaning in the present study. At the adult stage, we observed misalignment of CALB1 + Purkinje cells exposed to GBH, but the observed change was not statistically significant compared with that in the untreated controls.…”

Section: Discussionmentioning

confidence: 71%

Similar toxicity potential of glyphosate and glyphosate‐based herbicide on cerebellar development after maternal exposure in rats

Ojiro,

Ozawa,

Zou

et al. 2024

Environmental Toxicology

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Studies on the effects of glyphosate (GlyP) and glyphosate‐based herbicides (GBHs) on cerebellar development are extremely limited. This study examined the effects of maternal exposure to GlyP and GBH on rat cerebellar development in male offspring. From day 6 of gestation until day 21 postpartum at weaning, dams were given GlyP at 1.5% or 3.0% in diet or GBH at 1.0% in drinking water (corresponding to 0.36% GlyP). At weaning, GBH exposure was linked to increased numbers of DCX+ migrating granule cells in the cortex and TUNEL+ apoptotic cells in the internal granular layer (IGL), suggesting the disappearance of mismigrated granule cells via apoptosis. GBH also upregulated Nr4a3 and downregulated Cdk5 in the cerebellar vermis, suggesting a causal relation with the impaired granule cell development at this time. GlyP (3.0%) tended to increase in the number of DCX+ migrating granule cells in the IGL and upregulated Nr4a3 at weaning. Both compounds also upregulated genes related to granule cell migration (Astn1, Astn2, Nfia, and/or Nfix) at weaning and in adulthood, which might be an ameliorative response to delayed granule cell migration. Moreover, GBH induced Purkinje cell misalignment at weaning, which could be the result of delayed granule cell migration. In adulthood, GBH was associated with upregulation of the reelin signaling‐related genes Reln, Dab1, and Efnb1, suggesting a compensatory response to Purkinje cell misalignment. GlyP induced the same gene expression changes. These results suggest that GBH reversibly disrupts cerebellar development, primarily by targeting granule cell migration and differentiation, whereas GlyP exhibited similar toxic potential as GBH.

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“…In particular, it is known that CRMP1 is a semaphorin 3A signaling molecule, which mediates neuronal signaling in the developing brain and possesses the reelin-dependent regulation of neuronal migration in the cerebral cortex [110,111]. CRMP1 is also involved in Purkinje cell migration [112]. Reelin anomalies have long been associated with schizophrenia or behavioral control abnormalities [113].…”

Section: Crmp1mentioning

confidence: 99%

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders

Ochneva

Zorkina

Abramova

et al. 2022

IJMS

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Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders’ pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G).

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Loss of CRMP1 and CRMP2 results in migration defects of Purkinje cells in the X lobule of the mouse cerebellum

Cited by 5 publications

References 24 publications

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Similar toxicity potential of glyphosate and glyphosate‐based herbicide on cerebellar development after maternal exposure in rats

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders

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