Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes

Nishikawa, Masashi; Ito, Hidenori; Tabata, Hidenori; Ueda, Hiroshi; Nagata, Koh‐ichi

doi:10.3390/cells11040696

Cited by 6 publications

(4 citation statements)

References 41 publications

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“…In a rat model, prenatal BPA exposure was associated with altered expression of KCNQ3 in the amygdala of exposed females [39], and KCNQ3 may have important functions in some neurodevelopmental outcomes [40]. NAV2 guides axonal outgrowth and plays critical roles in early cerebellar development [41], while PLEKHG2 is also involved in axonal growth, and impaired function is likely involved in neuronal disorders [42]. Importantly, our study did not examine whether DNAm at our PFAS-associated epigenetic loci was associated with the expression of the genes or metabolites that we describe above.…”

Section: Discussionmentioning

confidence: 99%

Placental PFAS concentrations are associated with perturbations of placental DNA methylation at loci with important roles on cardiometabolic health

Everson,

Sehgal,

Barr

et al. 2024

Preprint

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The placenta is crucial for fetal development, is affected by PFAS toxicity, and evidence is accumulating that gestational PFAS perturb the epigenetic activity of the placenta. Gestational PFAS exposure is can adversely affect offspring, yet individual and cumulative impacts of PFAS on the placental epigenome remain underexplored. Here, we conducted an epigenome-wide association study (EWAS) to examine the relationships between placental PFAS levels and DNA methylation in a cohort of mother-infant dyads in Arkansas. We measured 17 PFAS in human placental tissues and quantified placental DNA methylation levels via the Illumina EPIC Microarray. We tested for differential DNA methylation with individual PFAS, and with mixtures of multiple PFAS. Our results demonstrated that numerous epigenetic loci were perturbed by PFAS, with PFHxS exhibiting the most abundant effects. Mixture analyses suggested cumulative effects of PFOA and PFOS, while PFHxS may act more independently. We additionally explored whether sex-specific effects may be present and concluded that future large studies should explicitly test for sex-specific effects. The genes that are annotated to our PFAS-associated epigenetic loci are primarily involved in growth processes and cardiometabolic health, while some genes are involved in neurodevelopment. These findings shed light on how prenatal PFAS exposures affect birth outcomes and children's health, emphasizing the importance of understanding PFAS mechanisms in the in-utero environment.

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Section: Discussionmentioning

confidence: 99%

Placental PFAS concentrations are associated with perturbations of placental DNA methylation at loci with important roles on cardiometabolic health

Everson,

Sehgal,

Barr

et al. 2024

Preprint

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“…Numbers indicate the positions from translational start sites. As a control RNAi vector, we used pSuper-Luc (sh-CTRL) designed against luciferase, CGTACGCGGAATACTTCGA (155–173) [ 9 ]. Glutathione-S-transferase (GST)-fused C-terminal fragment of Rich2 (aa 422–809; GST-Rich2-C) containing the epitope of anti-Rich2 (aa 465–492) was expressed in E. coli , purified, and used for the absorption experiment.…”

Section: Methodsmentioning

confidence: 99%

Expression Analyses of Rich2/Arhgap44, a Rho Family GTPase-Activating Protein, during Mouse Brain Development

et al. 2023

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Rho family small GTPases, such as Rho, Rac, and Cdc42, play essential roles during brain development, through regulating cellular signaling and actin cytoskeletal reorganization. Rich2/Arhgap44, a Rac- and Cdc42-specific GTPase-activating protein, has been reported to be a key regulator for dendritic spine morphology and synaptic function. Given the essential roles of Rac and Cdc42 in brain development, Rich2 is supposed to take part in brain development. However, not only the molecular mechanism involved, but also the expression profile of Rich2 during neurodevelopment has not yet been elucidated. In this study, we carried out expression analyses of Rich2 by focusing on mouse brain development. In immunoblotting, Rich2 exhibited a tissue-dependent expression profile in the young adult mouse, and the expression was increased during brain development. In immunohistochemical analyses, Rich2 was observed in the cytoplasm of cortical neurons at postnatal day (P) 0, and then came to be enriched in the nucleus with moderate distribution in neuropils at P7. Later at P30, complex immunostaining pattern of Rich2 was observed; Rich2 was distributed in the nucleus, cytoplasm and neuropils in many cortical neurons whereas other neurons frequently displayed little expression. In the hippocampus at P7, Rich2 was distributed mainly in the cytoplasm of excitatory neurons in the cornu ammonis regions while it was moderately detected in the nucleus in the dentate granule cells. Notably, Rich2 was distributed in excitatory synapses of the cornu ammonis 1 region at P30. Biochemical fractionation analyses also detected Rich2 in the postsynaptic density. Taken together, Rich2 is found to be expressed in the central nervous system in a developmental stage-dependent manner, and may be involved in synapse formation/maintenance in cortical neurons.

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“…Pull-down assays were performed as described previously 36 . A glutathione S-transferase (GST)-fused PBD of PAK1 was expressed in Escherichia coli BL21 (DE3) and purified using Glutathione Sepharose™ 4B (Cytiva, Marlborough, MA, USA) according to the manufacturer’s instructions 33 .…”

Section: Methodsmentioning

confidence: 99%

A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association

Seyama

Nishikawa

Uchiyama

et al. 2023

Sci Rep

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RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T > C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.

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Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes

Cited by 6 publications

References 41 publications

Placental PFAS concentrations are associated with perturbations of placental DNA methylation at loci with important roles on cardiometabolic health

Placental PFAS concentrations are associated with perturbations of placental DNA methylation at loci with important roles on cardiometabolic health

Expression Analyses of Rich2/Arhgap44, a Rho Family GTPase-Activating Protein, during Mouse Brain Development

A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association

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