scholarly journals Capicua Regulates Dendritic Morphogenesis Through Ets in Hippocampal Neurons in vitro

2021 ◽  
Vol 15 ◽  
Author(s):  
Keqin Li ◽  
Shuai Shao ◽  
Tongjie Ji ◽  
Min Liu ◽  
Lufeng Wang ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Dendritic Growth ◽  
Dendrite Growth ◽  
Loss Of Function ◽  
Ht22 Cells ◽  
Dendritic Morphogenesis ◽  
Growth Loss ◽  
Main Period

Capicua (Cic), a transcriptional repressor frequently mutated in brain cancer oligodendroglioma, is highly expressed in adult neurons. However, its function in the dendritic growth of neurons in the hippocampus remains poorly understood. Here, we confirmed that Cic was expressed in hippocampal neurons during the main period of dendritogenesis, suggesting that Cic has a function in dendrite growth. Loss-of-function and gain-of function assays indicated that Cic plays a central role in the inhibition of dendritic morphogenesis and dendritic spines in vitro. Further studies showed that overexpression of Cic reduced the expression of Ets in HT22 cells, while in vitro knockdown of Cic in hippocampal neurons significantly elevated the expression of Ets. These results suggest that Cic may negatively control dendrite growth through Ets, which was confirmed by ShRNA knockdown of either Etv4 or Etv5 abolishing the phenotype of Cic knockdown in cultured neurons. Taken together, our results suggest that Cic inhibits dendritic morphogenesis and the growth of dendritic spines through Ets.

scholarly journals Maf1 regulates dendritic morphogenesis and influences learning and memory

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Kui Chen ◽  
Liang Zhu ◽  
Lin Guo ◽  
Yuan-Bo Pan ◽  
Dong-Fu Feng
Keyword(s):  
Learning And Memory ◽  
Dendritic Spines ◽  
Mtor Signaling ◽  
Pten Expression ◽  
Luciferase Reporter ◽  
Downstream Effector ◽  
Dendritic Morphogenesis ◽  
First Time

Abstract Maf1, a general transcriptional regulator and mTOR downstream effector, is highly expressed in the hippocampus and cortex, but the function of Maf1 in neurons is not well elucidated. Here, we first demonstrate that Maf1 plays a central role in the inhibition of dendritic morphogenesis and the growth of dendritic spines both in vitro and in vivo. Furthermore, Maf1 downregulation paradoxically leads to activation of AKT-mTOR signaling, which is mediated by decreased PTEN expression. Moreover, we confirmed that Maf1 could regulate the activity of PTEN promoter by luciferase reporter assay, and proved that Maf1 could bind to the promoter of PTEN by ChIP-PCR experiment. We also demonstrate that expression of Maf1 in the hippocampus affects learning and memory in mice. Taken together, we show for the first time that Maf1 inhibits dendritic morphogenesis and the growth of dendritic spines through AKT-mTOR signaling by increasing PTEN expression.

scholarly journals The Protein Dendrite Arborization and Synapse Maturation 1 (Dasm-1) Is Dispensable for Dendrite Arborization

2008 ◽  
Vol 28 (8) ◽  
pp. 2782-2791 ◽  
Author(s):  
Archana Mishra ◽  
Boris Knerr ◽  
Sónia Paixão ◽  
Edgar R. Kramer ◽  
Rüdiger Klein
Keyword(s):  
Hippocampal Neurons ◽  
Critical Role ◽  
Dendritic Tree ◽  
Dendrite Growth ◽  
Immunoglobulin Superfamily ◽  
Genetic Ablation ◽  
Neuronal Connections ◽  
Synapse Maturation

ABSTRACT The development of a highly branched dendritic tree is essential for the establishment of functional neuronal connections. The evolutionarily conserved immunoglobulin superfamily member, the protein dendrite arborization and synapse maturation 1 (Dasm-1) is thought to play a critical role in dendrite formation of dissociated hippocampal neurons. RNA interference-mediated Dasm-1 knockdown was previously shown to impair dendrite, but not axonal, outgrowth and branching (S. H. Shi, D. N. Cox, D. Wang, L. Y. Jan, and Y. N. Jan, Proc. Natl. Acad. Sci. USA 101:13341-13345, 2004). Here, we report the generation and analysis of Dasm-1 null mice. We find that genetic ablation of Dasm-1 does not interfere with hippocampal dendrite growth and branching in vitro and in vivo. Moreover, the absence of Dasm-1 does not affect the modulation of dendritic outgrowth induced by brain-derived neurotrophic factor. Importantly, the previously observed impairment in dendrite growth after Dasm-1 knockdown is also observed when the Dasm-1 knockdown is performed in cultured hippocampal neurons from Dasm-1 null mice. These findings indicate that the dendrite arborization phenotype was caused by off-target effects and that Dasm-1 is dispensable for hippocampal dendrite arborization.

scholarly journals Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization

2001 ◽  
Vol 155 (1) ◽  
pp. 65-76 ◽  
Author(s):  
Junlin Teng ◽  
Yosuke Takei ◽  
Akihiro Harada ◽  
Takao Nakata ◽  
Jianguo Chen ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Hippocampal Neurons ◽  
Synergistic Effects ◽  
Primary Cultures ◽  
Perinatal Period ◽  
Cortical Layer ◽  
Microtubule Organization ◽  
Dendritic Morphogenesis

MAP1B and MAP2 are major members of neuronal microtubule-associated proteins (MAPs). To gain insights into the function of MAP2 in vivo, we generated MAP2-deficient (map2−/−) mice. They developed without any apparent abnormalities, which indicates that MAP2 is dispensable in mouse survival. Because previous reports suggest a functional redundancy among MAPs, we next generated mice lacking both MAP2 and MAP1B to test their possible synergistic functions in vivo. Map2−/−map1b−/− mice died in their perinatal period. They showed not only fiber tract malformations but also disrupted cortical patterning caused by retarded neuronal migration. In spite of this, their cortical layer maintained an “inside-out” pattern. Detailed observation of primary cultures of hippocampal neurons from map2−/−map1b−/− mice revealed inhibited microtubule bundling and neurite elongation. In these neurons, synergistic effects caused by the loss of MAP2 and MAP1B were more apparent in dendrites than in axons. The spacing of microtubules was reduced significantly in map2−/−map1b−/− mice in vitro and in vivo. These results suggest that MAP2 and MAP1B have overlapping functions in neuronal migration and neurite outgrowth by organizing microtubules in developing neurons both for axonal and dendritic morphogenesis but more dominantly for dendritic morphogenesis.

scholarly journals The 5-HT4 receptor interacts with adhesion molecule L1 to modulate morphogenic signaling in neurons

2021 ◽  
Vol 134 (4) ◽  
pp. jcs249193
Author(s):  
Simon Bennet Sonnenberg ◽  
Jonah Rauer ◽  
Christoph Göhr ◽  
Nataliya Gorinski ◽  
Sophie Kristin Schade ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Serotonin Receptor ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Mitogen Activated Protein Kinase ◽  
Physical Interaction ◽  
Dependent Manner

ABSTRACTMorphological remodeling of dendritic spines is critically involved in memory formation and depends on adhesion molecules. Serotonin receptors are also implicated in this remodeling, though the underlying mechanisms remain enigmatic. Here, we uncovered a signaling pathway involving the adhesion molecule L1CAM (L1) and serotonin receptor 5-HT4 (5-HT4R, encoded by HTR4). Using Förster resonance energy transfer (FRET) imaging, we demonstrated a physical interaction between 5-HT4R and L1, and found that 5-HT4R–L1 heterodimerization facilitates mitogen-activated protein kinase activation in a Gs-dependent manner. We also found that 5-HT4R–L1-mediated signaling is involved in G13-dependent modulation of cofilin-1 activity. In hippocampal neurons in vitro, the 5-HT4R–L1 pathway triggers maturation of dendritic spines. Thus, the 5-HT4R–L1 signaling module represents a previously unknown molecular pathway regulating synaptic remodeling.

scholarly journals Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Anna Rocchi ◽  
Silvio Sacchetti ◽  
Antonio De Fusco ◽  
Silvia Giovedi ◽  
Barbara Parisi ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Neurological Diseases ◽  
Synaptic Function ◽  
Inhibitory Synapses ◽  
Synapsin I ◽  
Loss Of Function ◽  
Reduced Density ◽  
Cytoplasmic Side

AbstractSynapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically isolated syndrome; however, the effects and fate of autoantibodies in neurons are still unexplored. We found that in vitro exposure of primary hippocampal neurons to patient’s autoantibodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synaptic transmission. These effects were reproduced with a purified SynI antibody and completely absent in SynI knockout neurons. Autoantibodies to SynI are internalized by FcγII/III-mediated endocytosis, interact with endogenous SynI, and promote its sequestration and intracellular aggregation. Neurons exposed to human autoantibodies to SynI display a reduced density of SVs, mimicking the SynI loss-of-function phenotype. Our data indicate that autoantibodies to intracellular antigens such as SynI can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction may contribute to the evolution and progression of autoimmune-mediated neurological diseases positive for SynI autoantibodies.

scholarly journals Distinct temporal expression of GW182 (TNRC6A) in neurons regulates dendritic arborization

2021 ◽  
Author(s):  
Bharti Nawalpuri ◽  
Arpita Sharma ◽  
Sumantra Chattarji ◽  
Ravi S. Muddashetty
Keyword(s):  
Expression Pattern ◽  
Translational Control ◽  
Hippocampal Neurons ◽  
Dendritic Growth ◽  
Temporal Expression ◽  
Critical Determinant ◽  
Dendritic Morphogenesis ◽  
Temporal Expression Pattern ◽  
Developing Neurons

Precise development of the dendritic architecture is a critical determinant of mature neuronal circuitry. MicroRNA-mediated regulation of protein synthesis plays a crucial role in dendritic morphogenesis but the role of miRISC protein components in this process is less studied. Here, we show an important role of a key miRISC protein GW182 paralog TNRC6A in the regulation of dendritic growth. We have identified a distinct brain region specific spatio-temporal expression pattern of GW182 during rat postnatal development. We found that the window of peak GW182 expression coincides with the period of extensive dendritic growth, both in the hippocampus and cerebellum. Perturbation of GW182 function during a specific temporal window resulted in reduced dendritic growth of cultured hippocampal neurons. Mechanistically, we show that GW182 modulates dendritic growth by regulating global somato-dendritic translation, and actin cytoskeletal dynamics of developing neurons. Furthermore, we found that GW182 affects dendritic architecture by regulating the expression of actin modulator LIMK1. Taken together, our data reveal a previously undescribed neurodevelopmental expression pattern of GW182 and its role in dendritic morphogenesis, through both translational control and actin cytoskeletal rearrangement.

scholarly journals Distinct temporal expression of GW182 in neurons regulates dendritic arborization

2020 ◽  
Author(s):  
Bharti Nawalpuri ◽  
Ravi Muddashetty
Keyword(s):  
Expression Pattern ◽  
Translational Control ◽  
Hippocampal Neurons ◽  
Dendritic Growth ◽  
Neuronal Development ◽  
Dendritic Morphology ◽  
Temporal Expression ◽  
Critical Determinant ◽  
Dendritic Morphogenesis

AbstractPrecise development of the dendritic architecture is a critical determinant of mature neuronal circuitry. MicroRNA-mediated regulation of protein synthesis plays a crucial role in dendritic morphogenesis but the role of miRISC protein components in this process is less studied. Here, we show an important role of a key miRISC protein GW182 in the regulation of dendritic growth. We have identified a distinct brain region specific Spatio-temporal expression pattern of GW182 during rat postnatal development. We found that the window of peak GW182 expression coincides with the period of extensive dendritic growth, both in the hippocampus and cerebellum. Perturbation of GW182 function during a specific temporal window resulted in reduced dendritic growth of cultured hippocampal neurons. Mechanistically, we show that GW182 modulates dendritic growth by regulating global somato-dendritic translation, and actin cytoskeletal dynamics of developing neurons. Furthermore, we found that GW182 affects dendritic architecture by regulating the expression of actin modulator LIMK1. Taken together, our data reveal a previously undescribed neurodevelopmental expression pattern of GW182 and its role in dendritic morphogenesis, through both translational control and actin cytoskeletal rearrangement.SummaryGW182 is a key component of miRNA induced silencing complex (miRISC). Nawalpuri et al. show that GW182 has a unique temporal expression profile during neuronal development. The developmentally controlled expression of GW182 influences dendritic morphology by regulating the expression of actin modulator LIMK1.

scholarly journals The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility

2008 ◽  
Vol 180 (5) ◽  
pp. 915-929 ◽  
Author(s):  
Ruwin Pandithage ◽  
Richard Lilischkis ◽  
Kai Harting ◽  
Alexandra Wolf ◽  
Britta Jedamzik ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Loss Of Function ◽  
Cyclin Dependent Kinases ◽  
Expression Arrays ◽  
Cellular Processes ◽  
Growth Cone Collapse ◽  
Cytoskeletal Dynamics

Cyclin-dependent kinases (Cdks) fulfill key functions in many cellular processes, including cell cycle progression and cytoskeletal dynamics. A limited number of Cdk substrates have been identified with few demonstrated to be regulated by Cdk-dependent phosphorylation. We identify on protein expression arrays novel cyclin E–Cdk2 substrates, including SIRT2, a member of the Sirtuin family of NAD+-dependent deacetylases that targets α-tubulin. We define Ser-331 as the site phosphorylated by cyclin E–Cdk2, cyclin A–Cdk2, and p35–Cdk5 both in vitro and in cells. Importantly, phosphorylation at Ser-331 inhibits the catalytic activity of SIRT2. Gain- and loss-of-function studies demonstrate that SIRT2 interfered with cell adhesion and cell migration. In postmitotic hippocampal neurons, neurite outgrowth and growth cone collapse are inhibited by SIRT2. The effects provoked by SIRT2, but not those of a nonphosphorylatable mutant, are antagonized by Cdk-dependent phosphorylation. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function, and they provide evidence for a novel regulatory circuitry involving Cdks, SIRT2, and microtubules.

scholarly journals A Human-Specific Schizophrenia Risk Tandem Repeat Affects Alternative Splicing of a Human-Unique Isoform AS3MTd2d3 and Mushroom Dendritic Spine Density

2020 ◽  
Author(s):  
Xin Cai ◽  
Zhi-Hui Yang ◽  
Hui-Juan Li ◽  
Xiao Xiao ◽  
Ming Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Tandem Repeat ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Variable Number ◽  
High Linkage Disequilibrium ◽  
Spine Density ◽  
Functional Variation ◽  
Human Specific

Abstract Recent advances in functional genomics have facilitated the identification of multiple genes and isoforms associated with the genetic risk of schizophrenia, yet the causal variations remain largely unclear. A previous study reported that the schizophrenia risk single-nucleotide polymorphism (SNP) rs7085104 at 10q24.32 was in high linkage disequilibrium (LD) with a human-specific variable number of tandem repeat (VNTR), and both were significantly associated with the brain mRNA expression of a human-unique AS3MTd2d3 isoform in Europeans and African Americans. In this study, we have shown the direct regulation of the AS3MTd2d3 mRNA expression by this VNTR through an in vitro minigene splicing assay, suggesting that it is likely a causative functional variation. Intriguingly, we have further confirmed that the VNTR and rs7085104 are significantly associated with AS3MTd2d3 mRNA expression in brains of Han Chinese donors, and rs7085104 is also associated with risk of schizophrenia in East Asians. Finally, the overexpression of AS3MTd2d3 in cultured primary hippocampal neurons results in significantly reduced densities of mushroom dendritic spines, implicating its potential functional impact. Considering the crucial roles of dendritic spines in neuroplasticity, these results reveal the potential regulatory impact of the schizophrenia risk VNTR on AS3MTd2d3 and provide insights into the underlying biological mechanisms.

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