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Microcephaly in Arhgef2 knockout mouse model (postnatal 6 weeks) (A) The brain weight and size were significantly decreased in Arhgef2À/À mice. n = 5-8 per genotype, ***p < 0.001, *p < 0.05, n.s.: no significant difference, unpaired t test. (B) Nissl staining of sagittal brain sections. Arhgef2À/À mice showed a reduced thickness of frontal and motor cortex region compared with wild-type ones, 30 mm thick; scale bar, 2.5 mm, n = 4 per genotype, **p < 0.01, *p < 0.05, unpaired t test. Data are represented as mean G S.D.
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N⁶-methyladenosine (m⁶A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of Arhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth and synaptic formation through regulating m⁶A methylation. Arhgef2 knockout decreases expression of Mettl...
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... we reported a homozygous ARHGEF2 mutation in individuals with a neurodevelopmental phenotype including brain malformation ( Ravindran et al., 2017). To explore the pathomechanism of brain malformation by loss of Arhgef2, we constructed an Arhgef2 knockout (Arhgef2À/À) mice model using CRISPR-Cas9 genome editing technology ( Figure S1). A 1.14-fold decrease in brain weight was noted in response to Arhgef2 knockout, whereas the body weight had no significant change. ...
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... 1.14-fold decrease in brain weight was noted in response to Arhgef2 knockout, whereas the body weight had no significant change. Compared with wild-type littermates, the brain size was significantly decreased in Arhgef2À/À mice ( Figure 1A). Nissl staining further exhibited reduced thickness of frontal and motor cortex in Arhgef2À/À mice ( Figure 1B). ...
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... with wild-type littermates, the brain size was significantly decreased in Arhgef2À/À mice ( Figure 1A). Nissl staining further exhibited reduced thickness of frontal and motor cortex in Arhgef2À/À mice ( Figure 1B). ...
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... we reported a homozygous ARHGEF2 mutation in individuals with a neurodevelopmental phenotype including brain malformation ( Ravindran et al., 2017). To explore the pathomechanism of brain malformation by loss of Arhgef2, we constructed an Arhgef2 knockout (Arhgef2À/À) mice model using CRISPR-Cas9 genome editing technology ( Figure S1). A 1.14-fold decrease in brain weight was noted in response to Arhgef2 knockout, whereas the body weight had no significant change. ...
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... 1.14-fold decrease in brain weight was noted in response to Arhgef2 knockout, whereas the body weight had no significant change. Compared with wild-type littermates, the brain size was significantly decreased in Arhgef2À/À mice ( Figure 1A). Nissl staining further exhibited reduced thickness of frontal and motor cortex in Arhgef2À/À mice ( Figure 1B). ...
Citations
... Elesheimer et al. found that the downregulated CEND1 expression leads to cognitive dysfunction via mitochondrial pathway [25]. Another study also found that the down-regulated CEND1 expression impaired neuronal differentiation, but the up-regulated CEND1 expression ameliorated it [26]. These results suggest that CEND1 is an important regulator of neuronal differentiation and neurodevelopment. ...
Brain injury in preterm infants is a major cause of disability and mortality in children. GSK-3β is a common pathogenic factor for cognitive dysfunction and involves in neuronal proliferation and differentiation. However, GSK-3β affected neuronal differentiation and its molecular pathogenesis after hypoxic-ischemic brain damage in neonatal rats remains unclear. This study investigated the effects of GSK-3β inhibitor (TWS119) on cell cycle regulatory proteins, a neuronal differentiation factor (CEND1), maturation neurons, T-box brain transcription factor 1 (TBR1)-positive neurons to clarify the mechanisms of hypoxic-ischemic brain damage in neonatal rats. We used hypoxic-ischemic Sprague–Dawley neonatal rats with brain damage as models. These rats were used for investigating the effect of GSK-3β on cell cycle regulatory proteins, neuronal differentiation factor (CEND1), maturation neurons, TBR1-positive neurons by western blot and immunofluorescence. Cyclin D1 (a positive cell cycle regulator) expression decreased, and p21 (a negative cell cycle regulator) expression increased in the TWS119 group compared to the hypoxia-ischemia (HI) group 7 days after HI. Additionally, compared to the HI group, TWS119 treatment up-regulated CEND1 expression and promoted neuronal differentiation and cortex development based on NeuN and TBR1 expression. Our study suggests that the GSK-3β inhibitor TWS119 promotes neuronal differentiation after hypoxic-ischemic brain damage in neonatal rats by inhibiting cell cycle pathway.
... The NF-κB repressing factor (Nkrfl) plays a critical role in maintaining nucleolar homeostasis by preventing aberrant precursors during rRNA processing (Coccia et al. 2017). Npdc1 regulates terminal neural differentiation, and its mRNA is a target of m(6)A methylation (Zhou et al. 2021). The Krab zinc finger protein Zfp68 was shown to be a transcription repressor, which helps establish the silencing histone mark H3K9me3 in partnership with Trim28 (Mun 2021). ...
Genomic imprinting is a parent-of-origin-specific expression phenomenon that plays fundamental roles in many biological processes. In animals, imprinting is only observed in therian mammals, with ∼200 imprinted genes known in humans and mice. The imprinting pattern in marsupials has been minimally investigated by examining orthologs to known eutherian imprinted genes. To identify marsupial-specific imprinting in an unbiased way, we performed RNA-seq studies on samples of fetal brain and placenta from the reciprocal cross progeny of two laboratory opossum stocks. We inferred allele-specific expression for >3000 expressed genes and discovered/validated 13 imprinted genes, including three previously known imprinted genes, Igf2r, Peg10, and H19. We estimate that marsupials imprint ∼60 autosomal genes, which is a much smaller set compared to eutherians. Among the nine novel imprinted genes, three noncoding RNAs have no known homologs in eutherian mammals, while the remaining genes have important functions in pluripotency, transcription regulation, nucleolar homeostasis, and neural differentiation. Methylation analyses at promoter CpG islands revealed differentially methylated regions in five of these marsupial-specific imprinted genes, suggesting that differential methylation is a common mechanism in the epigenetic regulation of marsupial imprinting. Clustering and co-regulation were observed at marsupial imprinting loci Pou5f3-Npdc1 and Nkrfl-Ipncr2, but eutherian-type multi-gene imprinting clusters were not detected. Also differing from eutherian mammals, the brain and placenta imprinting profiles are remarkably similar in opossums, presumably due to the shared origin of these organs from the trophectoderm. Our results contribute to a fuller understanding of the origin, evolution, and mechanisms of genomic imprinting in therian mammals.
... Here members of the ArhGEF family could play an important role. Recent studies unraveled that especially ArhGEF1 and ArhGEF2 are highly involved in the regulation of the dendritic development as activators of RhoA (Xiang et al., 2016(Xiang et al., , 2017Zhou et al., 2021). Other potential candidates are Ephexins as well as Trio which have important regulatory functions for the dendritogenesis (Wu et al., 2007;Iyer et al., 2012). ...
Vav proteins belong to the class of guanine nucleotide exchange factors (GEFs) that catalyze the exchange of guanosine diphosphate (GDP) by guanosine triphosphate (GTP) on their target proteins. Here, especially the members of the small GTPase family, Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 homolog (Cdc42) can be brought into an activated state by the catalytic activity of Vav-GEFs. In the central nervous system (CNS) of rodents Vav3 shows the strongest expression pattern in comparison to Vav2 and Vav1, which is restricted to the hematopoietic system. Several studies revealed an important role of Vav3 for the elongation and branching of neurites. However, little is known about the function of Vav3 for other cell types of the CNS, like astrocytes. Therefore, the following study analyzed the effects of a Vav3 knockout on several astrocytic parameters as well as the influence of Vav3-deficient astrocytes on the dendritic development of cultured neurons. For this purpose, an indirect co-culture system of native hippocampal neurons and Vav3-deficient cortical astrocytes was used. Interestingly, neurons cultured in an indirect contact with Vav3-deficient astrocytes showed a significant increase in the dendritic complexity and length after 12 and 17 days in vitro (DIV). Furthermore, Vav3-deficient astrocytes showed an enhanced regeneration in the scratch wound heal assay as well as an altered profile of released cytokines with a complete lack of CXCL11, reduced levels of IL-6 and an increased release of CCL5. Based on these observations, we suppose that Vav3 plays an important role for the development of dendrites by regulating the expression and the release of neurotrophic factors and cytokines in astrocytes.
