dendrite development
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2021 ◽  
Author(s):  
Fugui Niu ◽  
Peng Han ◽  
Jian Zhang ◽  
Yuanchu She ◽  
Lixin Yang ◽  
...  

AbstractThe precise control of growth and maintenance of the retinal ganglion cell (RGC) dendrite arborization is critical for normal visual functions in mammals. However, the underlying mechanisms remain elusive. Here we find that the m6A reader YTHDF2 is highly expressed in the mouse RGCs. Conditional knockout (cKO) of Ythdf2 in the retina leads to increased RGC dendrite branching, resulting in more synapses in the inner plexiform layer. Interestingly, the Ythdf2 cKO mice show improved visual acuity compared with control mice. We further demonstrate that Ythdf2 cKO in the retina protects RGCs from dendrite degeneration caused by the experimental acute glaucoma model. We identify the m6A-modified YTHDF2 target transcripts which mediate these effects. This study reveals mechanisms by which YTHDF2 restricts RGC dendrite development and maintenance. YTHDF2 and its target mRNAs might be valuable in developing new treatment approaches for glaucomatous eyes.Impact statementThe m6A reader YTHDF2 negatively regulates RGC dendrite branching through destabilizing its m6A-modified target mRNAs encoding proteins controlling dendrite development and maintenance. Ythdf2 cKO improves visual acuity and alleviates acute ocular hypertension-induced glaucoma in mice.


PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260005
Author(s):  
Monica C. Lannom ◽  
Joshua Nielsen ◽  
Aatiqa Nawaz ◽  
Temirlan Shilikbay ◽  
Stephanie Ceman

Fragile X syndrome results from the loss of expression of the Fragile X Mental Retardation Protein (FMRP). FMRP and RNA helicase Moloney Leukemia virus 10 (MOV10) are important Argonaute (AGO) cofactors for miRNA-mediated translation regulation. We previously showed that MOV10 functionally associates with FMRP. Here we quantify the effect of reduced MOV10 and FMRP expression on dendritic morphology. Murine neurons with reduced MOV10 and FMRP phenocopied Dicer1 KO neurons which exhibit impaired dendritic maturation Hong J (2013), leading us to hypothesize that MOV10 and FMRP regulate DICER expression. In cells and tissues expressing reduced MOV10 or no FMRP, DICER expression was significantly reduced. Moreover, the Dicer1 mRNA is a Cross-Linking Immunoprecipitation (CLIP) target of FMRP Darnell JC (2011), MOV10 Skariah G (2017) and AGO2 Kenny PJ (2020). MOV10 and FMRP modulate expression of DICER1 mRNA through its 3’untranslated region (UTR) and introduction of a DICER1 transgene restores normal neurite outgrowth in the Mov10 KO neuroblastoma Neuro2A cell line and branching in MOV10 heterozygote neurons. Moreover, we observe a global reduction in AGO2-associated microRNAs isolated from Fmr1 KO brain. We conclude that the MOV10-FMRP-AGO2 complex regulates DICER expression, revealing a novel mechanism for regulation of miRNA production required for normal neuronal morphology.


Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2777
Author(s):  
Lukas Kilo ◽  
Tomke Stürner ◽  
Gaia Tavosanis ◽  
Anna B. Ziegler

Neuronal dendrites receive, integrate, and process numerous inputs and therefore serve as the neuron’s “antennae”. Dendrites display extreme morphological diversity across different neuronal classes to match the neuron’s specific functional requirements. Understanding how this structural diversity is specified is therefore important for shedding light on information processing in the healthy and diseased nervous system. Popular models for in vivo studies of dendrite differentiation are the four classes of dendritic arborization (c1da–c4da) neurons of Drosophila larvae with their class-specific dendritic morphologies. Using da neurons, a combination of live-cell imaging and computational approaches have delivered information on the distinct phases and the time course of dendrite development from embryonic stages to the fully developed dendritic tree. With these data, we can start approaching the basic logic behind differential dendrite development. A major role in the definition of neuron-type specific morphologies is played by dynamic actin-rich processes and the regulation of their properties. This review presents the differences in the growth programs leading to morphologically different dendritic trees, with a focus on the key role of actin modulatory proteins. In addition, we summarize requirements and technological progress towards the visualization and manipulation of such actin regulators in vivo.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kathrin Spendier ◽  
Eugenia C. Olesnicky ◽  
Daniel Forand ◽  
Margaret Wolf ◽  
Darrell J. Killian

Abstract Objective RNA-binding proteins (RBPs) are important regulators of gene expression that influence mRNA splicing, stability, localization, transport, and translational control. In particular, RBPs play an important role in neurons, which have a complex morphology. Previously, we showed that there are many RBPs that play a conserved role in dendrite development in Drosophila dendritic arborization neurons and Caenorhabditis elegans (C. elegans) PVD neurons including the cytoplasmic polyadenylation element binding proteins (CPEBs), Orb in Drosophila and CPB-3 in C. elegans, and the DEAD box RNA helicases, Me31B in Drosophila and CGH-1 in C. elegans. During these studies, we observed that fluorescently-labeled CPB-3 and CGH-1 localize to cytoplasmic particles that are motile, and our research aims to further characterize these RBP-containing particles in live neurons. Results Here we extend on previous work to show that CPB-3 and CGH-1 localize to motile particles within dendrites that move at a speed consistent with microtubule-based transport. This is consistent with a model in which CPB-3 and CGH-1 influence dendrite development through the transport and localization of their mRNA targets. Moreover, CPB-3 and CGH-1 rarely localize to the same particles suggesting that these RBPs function in discrete ribonucleoprotein particles (RNPs) that may regulate distinct mRNAs.


2021 ◽  
Vol 22 (14) ◽  
pp. 7510
Author(s):  
Gum Hwa Lee ◽  
Seong-Eun Lee

Reelin is a secretory protein involved in a variety of processes in forebrain development and function, including neuronal migration, dendrite growth, spine formation, and synaptic plasticity. Most of the function of Reelin is focused on excitatory neurons; however, little is known about its effects on inhibitory neurons and inhibitory synapses. In this study, we investigated the phosphatidylinositol 3-kinase/Akt pathway of Reelin in primary cortical and hippocampal neurons. Individual neurons were visualized using immunofluorescence to distinguish inhibitory neurons from excitatory neurons. Reelin-rich protein supplementation significantly induced the phosphorylation of Akt and ribosomal S6 protein in excitatory neurons, but not in most inhibitory neurons. In somatostatin-expressing inhibitory neurons, one of major subtypes of inhibitory neurons, Reelin-rich protein supplementation induced the phosphorylation of S6. Subsequently, we investigated whether or not Reelin-rich protein supplementation affected dendrite development in cultured inhibitory neurons. Reelin-rich protein supplementation did not change the total length of dendrites in inhibitory neurons in vitro. Finally, we examined the development of inhibitory synapses in primary hippocampal neurons and found that Reelin-rich protein supplementation significantly reduced the density of gephyrin–VGAT-positive clusters in the dendritic regions without changing the expression levels of several inhibitory synapse-related proteins. These findings indicate a new role for Reelin in specific groups of inhibitory neurons and the development of inhibitory synapses, which may contribute to the underlying cellular mechanisms of RELN-associated neurological disorders.


2021 ◽  
pp. 100730
Author(s):  
Xiao-xiao Wang ◽  
Si Zhang ◽  
Ping-ping Dong ◽  
Yao-hua Li ◽  
Li Zhang ◽  
...  
Keyword(s):  

2021 ◽  
Author(s):  
Rui Chen ◽  
Quan Wang ◽  
Chongchong Xu ◽  
Qiang Wei ◽  
Hai Yang ◽  
...  

Abstract Schizophrenia (SCZ) is highly polygenic, and thousands of genes contribute to its risk. The 145 GWAS loci identified to date do not fully reveal SCZ genetic risk pathways. In this study, we explore a cost-effective strategy to increase power of inference of novel pathways, by expanding the analysis to include sub-threshold GWAS (subGWAS) loci. We identify 180 subGWAS loci (e.g., 5 x10-8 < P ≤ 10-6) based on SCZ summary statistics of 40,675 cases and 64,643 controls from CLOZUK and PGC datasets, and show that subGWAS loci contain substantial true genetic association signals. We merge GWAS (sigGWAS) and subGWAS loci and identify in total 304 high-confidence risk genes (HRGs) by jointly modeling the expanded set of loci. We identify dendrite development and morphogenesis (DDM, GO:0016358 and GO:0048813) as a novel category of biological processes implicated in SCZ genetic risk. SigGWAS loci fail to detect DDM, which is predominantly enriched in subGWAS loci. Further, DDM genes are significantly enriched for heritability of SCZ, as well as bipolar disorder and major depression. Genes in this functional process show cell type specificity in neurons in both fetal and adult brains, and their involvement in SCZ risk is further supported by eQTL analysis of SCZ risk alleles. We derived induced pluripotent stem cell (iPSC) lines from sporadic SCZ patients and normal controls and observe increased neurite lengths and soma sizes in patient-derived iPSC lines along multiple time points during neuronal development, further validating the genetic findings. We also find that the implicated genes are enriched in FDA-approved drug targets, suggesting a therapeutic potential for targeting the implicated biological processes for prevention and treatment. Our results showcase that expanding the analysis to include subGWAS loci is a valuable strategy for enhancing power of uncovering disease mechanisms, especially those of weak effect size, for SCZ and other complex diseases.


eNeuro ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. ENEURO.0193-20.2021
Author(s):  
Jie Yin Chua ◽  
Shi Jun Ng ◽  
Oleksandr Yagensky ◽  
Erich E. Wanker ◽  
John Jia En Chua
Keyword(s):  

Author(s):  
Mitsuharu Hattori ◽  
Takao Kohno

Abstract The secreted glycoprotein Reelin plays important roles in both brain development and function. During development, Reelin regulates neuronal migration and dendrite development. In the mature brain, the glycoprotein is involved in synaptogenesis and synaptic plasticity. It has been suggested that Reelin loss or decreased function contributes to the onset and/or deterioration of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease. While the molecular mechanisms underpinning Reelin function remain unclear, recent studies have suggested that the specific proteolytic cleavage of Reelin may play central roles in the embryonic and postnatal brain. In this review, we focus on Reelin proteolytic processing and review its potential physiological roles.


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