Drebrin regulates cytoskeleton dynamics in migrating neurons through interaction with CXCR4

Stromal cell-derived factor-1 (SDF-1) and chemokine receptor type 4 (CXCR4) are regulators of neuronal migration (e.g., GnRH neurons, cortical neurons, and hippocampal granule cells). However, how SDF-1/CXCR4 alters cytoskeletal components remains unclear. Developmentally regulated brain protein (drebrin) stabilizes actin polymerization, interacts with microtubule plus ends, and has been proposed to directly interact with CXCR4 in T cells. The current study examined, in mice, whether CXCR4 under SDF-1 stimulation interacts with drebrin to facilitate neuronal migration. Bioinformatic prediction of protein–protein interaction highlighted binding sites between drebrin and crystallized CXCR4. In migrating GnRH neurons, drebrin, CXCR4, and the microtubule plus-end binding protein EB1 were localized close to the cell membrane. Coimmunoprecipitation (co-IP) confirmed a direct interaction between drebrin and CXCR4 using wild-type E14.5 whole head and a GnRH cell line. Analysis of drebrin knockout (DBN1 KO) mice showed delayed migration of GnRH cells into the brain. A decrease in hippocampal granule cells was also detected, and co-IP confirmed a direct interaction between drebrin and CXCR4 in PN4 hippocampi. Migration assays on primary neurons established that inhibiting drebrin (either pharmacologically or using cells from DBN1 KO mice) prevented the effects of SDF-1 on neuronal movement. Bioinformatic prediction then identified binding sites between drebrin and the microtubule plus end protein, EB1, and super-resolution microscopy revealed decreased EB1 and drebrin coexpression after drebrin inhibition. Together, these data show a mechanism by which a chemokine, via a membrane receptor, communicates with the intracellular cytoskeleton in migrating neurons during central nervous system development.

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Common binding by redundant group B Sox proteins is evolutionarily conserved in Drosophila

10.1101/012872 ◽

2014 ◽

Author(s):

Sarah H Carl ◽

Steven Russell

Keyword(s):

Binding Site ◽

Binding Sites ◽

Regulatory Networks ◽

System Development ◽

Nervous System Development ◽

Phylogenetic Distance ◽

Functional Sites ◽

Sox Proteins ◽

Alternative Sources ◽

Group B

Background: Group B Sox proteins are a highly conserved group of transcription factors that act extensively to coordinate nervous system development in higher metazoans while showing both co-expression and functional redundancy across a broad group of taxa. In Drosophila melanogaster, the two group B Sox proteins Dichaete and SoxNeuro show widespread common binding across the genome. While some instances of functional compensation have been observed in Drosophila, the function of common binding and the extent of its evolutionary conservation is not known. Results: We used DamID-seq to examine the genome-wide binding patterns of Dichaete and SoxNeuro in four species of Drosophila. Through a quantitative comparison of Dichaete binding, we evaluated the rate of binding site turnover across the genome as well as at specific functional sites. We also examined the presence of Sox motifs within binding intervals and the correlation between sequence conservation and binding conservation. To determine whether common binding between Dichaete and SoxNeuro is conserved, we performed a detailed analysis of the binding patterns of both factors in two species. Conclusion: We find that, while the regulatory networks driven by Dichaete and SoxNeuro are largely conserved across the drosophilids studied, binding site turnover is widespread and correlated with phylogenetic distance. Nonetheless, binding is preferentially conserved at known cis-regulatory modules and core, independently verified binding sites. We observed the strongest binding conservation at sites that are commonly bound by Dichaete and SoxNeuro, suggesting that these sites are functionally important. Our analysis provides insights into the evolution of group B Sox function, highlighting the specific conservation of shared binding sites and suggesting alternative sources of neofunctionalisation between paralogous family members.

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Amoeboid-like neuronal migration ensures correct horizontal cell layer formation in the developing vertebrate retina

10.1101/2021.10.15.464510 ◽

2021 ◽

Author(s):

Rana Amini ◽

Raimund Schlüßler ◽

Stephanie Möllmert ◽

Archit Bhatnagar ◽

Jochen Guck ◽

...

Keyword(s):

Neuronal Migration ◽

System Development ◽

Horizontal Cell ◽

Nervous System Development ◽

Horizontal Cells ◽

Layer Formation ◽

Tissue Architecture ◽

Nucleus Shape ◽

Cell Tissue ◽

Shape Changes

As neurons are often born at positions different than where they ultimately function, neuronal migration is key to ensure successful nervous system development. Radial migration during which neurons featuring unipolar and bipolar morphology, employ pre-existing processes or underlying cells for directional guidance, is the most well explored neuronal migration mode. However, how neurons that display multipolar morphology, without such processes, move through highly crowded tissue environments towards their final positions remains elusive. To understand this, we here investigated multipolar migration of horizontal cells in the zebrafish retina. We found that horizontal cells tailor their movements to the environmental spatial constraints of the crowded retina, by featuring several characteristics of amoeboid migration. These include cell and nucleus shape changes, and persistent rearward polarization of stable F-actin, which enable horizontal cells to successfully move through the crowded retina. Interference with the organization of the developing retina by changing nuclear properties or overall tissue architecture, hampers efficient horizontal cell migration and layer formation. Thus, cell-tissue interplay is crucial for efficient migration of horizontal cells in the retina. In view of high proportion of multipolar neurons, the here uncovered ameboid-like neuronal migration mode might also be crucial in other areas of the developing brain.

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Direct interaction of Sox10 with cadherin-19 mediates early sacral neural crest cell migration: implications for enteric nervous system development defects

Gastroenterology ◽

10.1053/j.gastro.2021.08.029 ◽

2021 ◽

Author(s):

Taida Huang ◽

Yonghui Hou ◽

Xia Wang ◽

Liang Wang ◽

Chenju Yi ◽

...

Keyword(s):

Nervous System ◽

Cell Migration ◽

System Development ◽

Neural Crest Cell ◽

Direct Interaction ◽

Nervous System Development ◽

Neural Crest Cell Migration ◽

Sacral Neural Crest ◽

Crest Cell ◽

Enteric Nervous System Development

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Eph-ephrin signaling in nervous system development

F1000Research ◽

10.12688/f1000research.7417.1 ◽

2016 ◽

Vol 5 ◽

pp. 413 ◽

Cited By ~ 22

Author(s):

Karina S. Cramer ◽

Ilona J. Miko

Keyword(s):

Nervous System ◽

Signaling Pathways ◽

Neuronal Migration ◽

System Development ◽

Nervous System Development ◽

Eph Receptors ◽

Binding Affinities ◽

Developmental Processes ◽

Axon Targeting

Ephrins and Eph receptors enable contact-mediated interactions between cells at every stage of nervous system development. In spite of their broad binding affinities, Eph proteins facilitate specificity in neuronal migration and axon targeting. This review focuses on recent studies that demonstrate how these proteins interact with each other, and with other signaling pathways, to guide specificity in a diverse set of developmental processes.

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Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2

Molecular Biology of the Cell ◽

10.1091/mbc.e05-07-0700 ◽

2006 ◽

Vol 17 (3) ◽

pp. 1273-1285 ◽

Cited By ~ 76

Author(s):

Takashi Nishimura ◽

Tomoya Yamaguchi ◽

Akinori Tokunaga ◽

Akitoshi Hara ◽

Tomonari Hamaguchi ◽

...

Keyword(s):

Dendritic Spine ◽

Hippocampal Neurons ◽

Neuronal Development ◽

System Development ◽

Direct Interaction ◽

Nervous System Development ◽

Nucleotide Exchange ◽

Spine Development

Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2.

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Multiple Functional Neurosteroid Binding Sites on GABAA Receptors

10.1101/357574 ◽

2018 ◽

Cited By ~ 2

Author(s):

Zi-Wei Chen ◽

John R. Bracamontes ◽

Melissa M. Budelier ◽

Allison L. Germann ◽

Daniel J. Shin ◽

...

Keyword(s):

Binding Sites ◽

Neuronal Excitability ◽

System Development ◽

Docking Studies ◽

Ring Structure ◽

Nervous System Development ◽

Computational Docking ◽

Anesthetic Agents ◽

Electrophysiological Studies ◽

Endogenous Modulators

AbstractNeurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While GABAA receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill-defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry, we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3GABAA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1 and β3 subunits, adjacent to the extracellular domains. An intersubunit site in the interface between the β3(+) and α1(-) subunits of the GABAA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAA receptors. Electrophysiological studies based on these predictions indicate that both the α1 intrasubunit and β3-α1 intersubunit sites are critical for neurosteroid action.

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Transcriptional profiling of iPSC-derived neurons with reciprocal monogenic CNV in 3p26.3 region

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.03.10-11 ◽

2020 ◽

pp. 10-11

Author(s):

М.Е. Лопаткина ◽

В.С. Фишман ◽

М.М. Гридина ◽

Н.А. Скрябин ◽

Т.В. Никитина ◽

...

Keyword(s):

Gene Expression ◽

Copy Number ◽

System Development ◽

Transcriptional Profiling ◽

Global Gene Expression ◽

Nervous System Development ◽

Number Variation ◽

The Central Nervous System ◽

Cntn6 Gene ◽

Copy Number Changes

Проведен анализ генной экспрессии в нейронах, дифференцированных из индуцированных плюрипотентных стволовых клеток пациентов с идиопатическими интеллектуальными нарушениями и реципрокными хромосомными мутациями в регионе 3p26.3, затрагивающими единственный ген CNTN6. Для нейронов с различным типом хромосомных аберраций была показана глобальная дисрегуляция генной экспрессии. В нейронах с вариациями числа копий гена CNTN6 была снижена экспрессия генов, продукты которых вовлечены в процессы развития центральной нервной системы. The gene expression analysis of iPSC-derived neurons, obtained from patients with idiopathic intellectual disability and reciprocal microdeletion and microduplication in 3p26.3 region affecting the single CNTN6 gene was performed. The global gene expression dysregulation was demonstrated for cells with CNTN6 copy number variation. Gene expression in neurons with CNTN6 copy number changes was downregulated for genes, whose products are involved in the central nervous system development.

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Exogenous Neonatal Erythropoietin Mitigates Brain Damage After a Combination of Prenatal Hypoxic-Ischemia and Lipopolysaccharide Inflammation in Rats

Journal of Neurosurgery Pediatrics ◽

10.3171/ped/2008/1/4/paper9 ◽

2008 ◽

Vol 1 (4) ◽

pp. A353

Author(s):

Shenandoah Robinson ◽

Qing Li

Keyword(s):

Brain Damage ◽

Intracellular Signaling ◽

System Development ◽

Intrauterine Infection ◽

Artery Occlusion ◽

Nervous System Development ◽

Human Infants ◽

Hypoxic Ischemia ◽

Show Evidence ◽

The Impact

Introduction Many infants born very preterm who suffer brain damage most likely experienced a combined insult from intrauterine infection and placental insufficiency. Damage is thought to be synergistic rather than additive but the mechanisms of combined injury remain elusive. A combination of lipopolysaccharide-induced inflammation and hypoxia-ischemia has been used in rats to model the dual insult that occurs in human infants prenatally. Erythropoietin, a pleiotrophic cytokine that is essential for central nervous system development, ameliorates brain injury after isolated hypoxic-ischemic or inflammatory insults through different intracellular signaling pathways. We hypothesized that exogenous neonatal EPO administration would lessen the damage of a combined prenatal insult in rats. Methods On embryonic Day 18 fetal rats experienced 60 minutes of transient uterine artery occlusion with or without intracervical LPS administration with sham controls receiving surgery but no occlusion and saline for LPS. Survival was recorded and histological biochemical and functional assays were performed. Means were compared with ANOVA with Tukey HSD post hoc analysis. Results After a combined insult of HI and 0.15-mg/kg LPS on E18 the survival of pups by postnatal Day 1 (P1) decreased from 77% with HI alone to 22% for LPS plus HI. When exogenous systemic EPO was administered P1–P3 survival to P9 improved markedly from 40% (2 of 5) for saline-treated insult pups to 100% (6 of 6) for EPO-treated. Initial histological analyses show EPO decreases the number of brain activated caspase 3 and activated microglia by P9. Additional analyses will be presented. Conclusion As at least 60% of placentas from infants born pre-term show evidence of chorioamnionitis, assessment of the impact of exogenous EPO on a model of a combination injury is essential prior to proceeding with a clinical trial. Initial results indicate neonatal exogenous EPO mitigates damage from the combined insult.

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