PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5

Schaffer, Thomas; Smith, Jaclyn E.; Cook, Emily K.; Phan, Thao P; Margolis, Seth S.

doi:10.1016/j.celrep.2018.11.005

Cited by 15 publications

(14 citation statements)

References 61 publications

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“…(ARHGEF5/TIM1), Ephexin4 (ARH GEF16), and Ephexin5 (ARHGEF15/Vsm-RhoGEF) 9,21,[29][30][31][32] . It has been reported that Ephexin1 and Ephexin5 are phosphorylated by Src or Eph receptors but not ARH-GEF16 21,29,33 .…”

Section: Discussionmentioning

confidence: 99%

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FYN is required for ARHGEF16 to promote proliferation and migration in colon cancer cells

Chen

et al. 2020

Cell Death Dis

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ARHGEF16 is a recently identified Rho-family guanine nucleotide exchange factor (GEF) that has been implicated in the activation of Rho-family GTPases such as Rho G, Rac, and Cdc42. However, its functions in colon cancer cell proliferation and migration are not well understood. In this study, we showed that ARHGEF16 was highly expressed in clinical specimens of colon cancer. In colon cancer cells, ARHGEF16-stimulated proliferation and migration in vitro and in vivo. Furthermore, we identified a nonreceptor tyrosine kinase, FYN, as a novel partner of ARHGEF16. Knocking down FYN expression decreased ARHGEF16 protein level in colon cancer cells. We further demonstrated that ARHGEF16-induced colon cancer cell proliferation and migration were dependent on FYN since knockdown FYN abolished the ARHGEF16-induced proliferation and migration of colon cancer cells. The FYN-ARHGEF16 axis mediates colon cancer progression and is a potential therapeutic target for colon cancer treatment.

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Section: Discussionmentioning

confidence: 99%

“…The Ephexin subfamily comprises five members: Ephexin1 (ARHGEF27/ NGEF), Ephexin2 (ARHGEF19/WGEF), Ephexin3 (ARHGEF5/TIM1), Ephexin4 (ARHGEF16), and Ephexin5 (ARHGEF15/Vsm-RhoGEF) 9 , 21 , 29 – 32 . It has been reported that Ephexin1 and Ephexin5 are phosphorylated by Src or Eph receptors but not ARHGEF16 21 , 29 , 33 .…”

Section: Discussionmentioning

confidence: 99%

FYN is required for ARHGEF16 to promote proliferation and migration in colon cancer cells

Chen

et al. 2020

Cell Death Dis

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“…A previous study with hippocampal slices from mice showed that protein kinase C (PKC) delta increases, whereas PKC epsilon decreases, sensitivity of IPSCs to acute ethanol (80 mM) exposure (including duration of ethanol’s potentiation) 54 . These PKC isoforms have been demonstrated to be expressed in the hippocampus of P6 mice 55 . Future studies should determine whether the relative activity levels of these kinases in vicinity of GABA A receptors modulate their sensitivity to ethanol during early postnatal development.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Parvalbumin Interneuron-Mediated Neurotransmission in the Retrosplenial Cortex of Adolescent Mice Following Third Trimester-Equivalent Ethanol Exposure

Bird

Chavez

Barber

et al. 2020

Preprint

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Prenatal ethanol exposure causes a variety of cognitive deficits that have a persistent impact on quality of life, some of which may be explained by ethanol-induced alterations in interneuron function. Studies from several laboratories, including our own, have demonstrated that a single binge-like ethanol exposure during the third-trimester equivalent of human pregnancy leads to acute apoptosis and long-term loss of interneurons in the rodent retrosplenial cortex (RSC). The RSC is interconnected with the hippocampus, thalamus, and other neocortical regions and plays distinct roles in visuospatial processing and storage and retrieval of hippocampal-dependent episodic memories. Here we used slice electrophysiology to characterize the acute effects of ethanol on GABAergic neurotransmission in neonates, as well as the long-term effects of neonatal ethanol exposure on parvalbumin-interneuron mediated neurotransmission in adolescent mice. Mice were exposed to ethanol using vapor inhalation chambers. In postnatal day (P) 7 mouse pups, ethanol unexpectedly failed to potentiate GABA A receptor-mediated synaptic transmission. Binge-like ethanol exposure of P7 mice expressing channel rhodopsin in parvalbumin-positive interneurons enhanced the peak amplitudes, total charge, decays, and decreased rise-times of optically-evoked GABA A receptor-mediated inhibitory postsynaptic currents in adolescent animals. These effects could partially explain learning and memory deficits caused by developmental ethanol exposure. Experiment 2 AnimalsMice expressing the channel rhodopsin-2 (ChR2) variant ChR2 H134R fused to tdTomato in PV-INs were generated by crossing female heterozygous B6.129P2-Pvalb tm1(cre)Arbr /J (B6 PV cre , Jackson Laboratory, Bar Harbor, ME; stock number 017320) and male heterozygous B6.Cg-Gt(ROSA)26Sor tm27.1(CAG-COP4*H134R/tdTomato)Hze /J (Ai27D, Jackson Laboratory; stock number 012567) mice. After weaning, the offspring (hereafter referred to as B6 PV cre -Ai27D mice) were ear-tagged and tail snips were collected under isoflurane anesthesia. Genotyping was performed by Transnetyx (Cordova, TN). Male and female mice aged between P40 and P60 were used for all subsequent experiments ( Figure 1b). Ethanol vapor chamber exposurePups and dams were exposed to either air or vaporized ethanol (95%, Koptec, King of Prussia, PA) for 4 h (approximately 10 a.m. to 2 p.m.) at P7 in custom-built ethanol vapor chambers 25 . Ethanol vapor concentrations were determined using a breathalyzer (Intoximeters, St. Louis, MO) and were between 8-9 g/dl. This exposure paradigm produces peak BECs in pups near 80 mM and triggers apoptotic neurodegeneration in several brain regions, including the RSC 13,18 . Immunohistochemistry 1 0

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“…Perhaps changes in the expression of these proteins might be responsible for the correct distribution of PSD-95. In this respect, it has been described that PKC isoforms acting through GEFs (Guanine nucleotide exchange factors which are activators of small GTPases) are able to modulate dendrite spine morphology (Schaffer et al, 2018). For example, PKCγ, the main PKC isoform involved in the morphological changes mediated by CD40L reverse signaling in MSNs (Carriba and Davies, 2017), phosphorylates βPIX (Pakinteracting exchange factor-β), a GEF protein that regulates Cdc42/Rac1 signaling (Shirafuji et al, 2014).…”

Section: Differences In the Expression Of Rhomentioning

confidence: 99%

CD40L Reverse Signaling Influences Dendrite Spine Morphology and Expression of PSD-95 and Rho Small GTPases

Carriba

Wyatt

Davies

2020

Front. Cell Dev. Biol.

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CD40-activated CD40L reverse signaling is a major physiological regulator of neural process growth from many kinds of developing neurons. Here we have investigated whether CD40L-reverse signaling also influences dendrite spine number and morphology in striatal medium spiny neurons (MSNs). Golgi preparations revealed no differences in the spine density, but because the dendrite arbors of MSNs were larger and branched in Cd40 −/− mice, the total number of spines was greater in Cd40 −/− mice. We also detected more mature spines compared with wild-type littermates. Western blot revealed that MSN cultures from Cd40 −/− mice had significantly less PSD-95 and there were changes in RhoA/B/C and Cdc42. Immunocytochemistry revealed that PSD-95 was clustered in spines in Cd40 −/− neurons compared with more diffuse labeling in Cd40 +/+ neurons. Activation of CD40L-reverse signaling with CD40-Fc prevented the changes observed in Cd40 −/− cultures. Our findings suggest that CD40L-reverse signaling influences dendrite spine morphology and related protein expression and distribution.

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PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5

Cited by 15 publications

References 61 publications

FYN is required for ARHGEF16 to promote proliferation and migration in colon cancer cells

FYN is required for ARHGEF16 to promote proliferation and migration in colon cancer cells

Enhancement of Parvalbumin Interneuron-Mediated Neurotransmission in the Retrosplenial Cortex of Adolescent Mice Following Third Trimester-Equivalent Ethanol Exposure

CD40L Reverse Signaling Influences Dendrite Spine Morphology and Expression of PSD-95 and Rho Small GTPases

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