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Disorganization and reduced numbers of hippocampal interneurons in 3 lox/ Dlx5/6-CIE, netrin-1 / mutants at P0. (A-H) A reduction in the number and organization of EGFP interneurons throughout the hippocampal subfields of 3 lox/ Dlx5/6-CIE, netrin-1 / double mutants is evident (D and H, arrow) compared with controls (A and E). (Scale bar, 500 m.)
Source publication
Cortical GABAergic interneurons, most of which originate in the ganglionic eminences, take distinct tangential migratory trajectories into the developing cerebral cortex. However, the ligand-receptor systems that modulate the tangential migration of distinct groups of interneurons into the emerging cerebral wall remain unclear. Here, we show that n...
Contexts in source publication
Context 1
... placed over the ganglionic eminences of E14.5 wild-type or netrin-1-mutant coronal brain slices. Neuronal migration from the explants onto distinct domains of cortical substrates was assessed 72 h later. 3 integrin-deficient interneu- rons displayed significant deficits in their ability to migrate onto cortical slices in the absence of netrin-1 ( Fig. S5 A, D, E, H, and I). A 25% (SD0.06) reduction in interneurons traversing the upper cortical plate was noticed (Fig. S5 A, D, E, H, and J). Neuronal migration from wild-type explants onto netrin-1-deficient slices was not affected (Fig. S5 A, C, E, G, and I). Together, these real-time interneuronal migration analyses and slice co-culture ...
Context 2
... the explants onto distinct domains of cortical substrates was assessed 72 h later. 3 integrin-deficient interneu- rons displayed significant deficits in their ability to migrate onto cortical slices in the absence of netrin-1 ( Fig. S5 A, D, E, H, and I). A 25% (SD0.06) reduction in interneurons traversing the upper cortical plate was noticed (Fig. S5 A, D, E, H, and J). Neuronal migration from wild-type explants onto netrin-1-deficient slices was not affected (Fig. S5 A, C, E, G, and I). Together, these real-time interneuronal migration analyses and slice co-culture assays suggest that netrin-1-3 integrin signaling facilitates inter- neuronal migration in the developing cerebral cortex, ...
Context 3
... displayed significant deficits in their ability to migrate onto cortical slices in the absence of netrin-1 ( Fig. S5 A, D, E, H, and I). A 25% (SD0.06) reduction in interneurons traversing the upper cortical plate was noticed (Fig. S5 A, D, E, H, and J). Neuronal migration from wild-type explants onto netrin-1-deficient slices was not affected (Fig. S5 A, C, E, G, and I). Together, these real-time interneuronal migration analyses and slice co-culture assays suggest that netrin-1-3 integrin signaling facilitates inter- neuronal migration in the developing cerebral cortex, specifically the subset of interneurons migrating through the top of the cortical ...
Context 4
... positioning in the hippocampal cortex provides an- other reliable measure of defects in long-distance interneuronal migration through the marginal zone region. We find a significant reduction in the number and organization of EGFP interneurons throughout the hippocampus in 3 lox/ Dlx5/6-CIE, netrin-1 / dou- ble mutants compared with controls ( Fig. 5 A, D, E, and H). In sum, these analyses of interneuronal organization indicate that netrin- 1-3 integrin interactions are necessary for the appropriate migra- tion and positioning of distinct subsets of interneurons within the developing cerebral ...
Citations
... Since the integrin α3 is an accomplice of integrin β1, the integrin α3β1 ligands exert influence on neuronal development, structure, regeneration, maintenance, and plasticity. 31,32 Nonetheless, our study did not explore the role of integrin β1 in rTMS-induced motor recovery post-stroke. ...
Background
Repetitive transcranial magnetic stimulation (rTMS) is an effective therapy in post‐stroke motor recovery. However, the underlying mechanisms of rTMS regulates long‐lasting changes with synaptic transmission and glutamate receptors function (including AMPARs or NMDARs) remains unclear.
Methods
Mice were received 10‐Hz rTMS treatment once daily on the third day after photothrombotic (PT) stroke for 18 days. Motor behaviors and the Western blot were used to evaluate the therapeutic efficacy of 10‐Hz rTMS in the mice with PT model. Moreover, we used wild‐type (WT) and NEX‐α3−/− mice to further explore the 10‐Hz rTMS effect.
Results
We found that 10‐Hz rTMS improved the post‐stroke motor performance in the PT mice. Moreover, the levels of AMPAR, vGlut1, and integrin α3 in the peri‐infarct were significantly increased in the rTMS group. In contrast, 10‐Hz rTMS did not induce these aforementioned effects in NEX‐α3−/− mice. The amplitude of AMPAR‐mediated miniature excitatory postsynaptic currents (EPSCs) and evoked EPSCs was increased in the WT + rTMS group, but did not change in NEX‐α3−/− mice with rTMS.
Conclusions
In this study, 10‐Hz rTMS improved the glutamatergic synaptic transmission in the peri‐infract cortex through effects on integrin α3 and AMPARs, which resulted in motor function recovery after stroke.
... Desde ese momento, ha sido involucrada como molécula de guía en múltiples regiones del cerebro actuando sobre multitud de tipos celulares. Así, netrina-1 se convirtió en una de las proteínas mejor estudiadas no sólo en el campo de la guía de los axones, sino que también se ha descrito que juega diferentes papeles en la formación del sistema nervioso, tales como sinaptogénesis(10-12), migraciones neuronales (13,14), supervivencia (15) ...
The brain is the most complex organ we have, and it is the one that defines us as human beings. It is the basis of intelligence, of our thoughts and memories. In addition, it interprets the world through the senses, initiates movement and controls our behaviors. The correct functioning of this organ is based on the correct establishment of connectivity patterns between the millions of neurons which enable a precise and efficient communication between them. These neural networks emerge during embryonic and postnatal development. The formation of proper neuronal circuitry relies on diverse and very precisely orchestrated events controlled by specific molecular mechanisms. Therefore, failures in these early events will lead to brain pathologies and complex disorders. In the last decades, remarkable progress has been made in identifying and in understanding the mechanisms of action of the molecular that direct axon and neural circuitry development. However, their role in vivo in many aspects of neural circuit formation remains largely unknown, particularly how the impairment of this initial connectivity derives in complex neurodevelopmental pathologies. Here, I highlight part of my contributions and recent advances that shed light on the complexity of mechanisms that regulate axon guidance and the wiring of the bilateral circuits of the central nervous system. Furthermore, I discuss about how understanding the development of bilateral circuits of the cerebellum is essential to understand the emergence of diverse neurodevelopmental pathologies.
... The coordination of ECM and cytoskeleton can initiate cell polarization and provide grounds for neuronal migration and lamination by affecting different modes of cellular migration, such as radial, tangential and chain migration, in distinct ways and controlling specifi c aspects of neuronal migration. For example, laminins is an ECM glycoprotein that have active roles in promoting neuronal migration through binding to cell surface receptors such as integrin and then transducing information to the cytoskeleton (Belvindrah et al. 2007 ;Chen et al. 2009 ;Mobley et al. 2009 ;Stanco et al. 2009 ). Reelin is an extracellular molecule secreted by Cajal-Retzius cells, and its binding to its receptors induces a series of phosphorylated signaling cascade that regulates microtubule dynamics and triggers neurons to migrate into their proper destination in the cortex (Beffert et al. 2004 ;D'Arcangelo et al. 1999 ;Gonzalez-Billault et al. 2005 ;Hiesberger et al. 1999 ;Howell et al. 2000 ). ...
Proper lamination of the cerebral cortex is precisely orchestrated, especially when neurons migrate from their place of birth to their fi nal destination. The consequences of failure or delay in neuronal migration cause a wide range of disorders, such as lissencephaly, schizophrenia, autism and mental retardation. Neuronal migration is a dynamic process, which requires dynamic remodeling of the cytoskeleton. In this context microtubules and microtu-bule-related proteins have been suggested to play important roles in the regulation of neuronal migration. Here, we will review the dynamic aspects of neuronal migration and brain development, describe the molecular and cellular mechanisms of neuronal migration and elaborate on neuronal migration diseases.
... Il est donc absolument nécessaire de continuer à développer de nouvelles Figure 1B) [6][7][8], même si peu de travaux ont finalement confirmé la pertinence de ces possibles récepteurs alternatifs. Outre ces récepteurs, la nétrine-1 peut également se lier à d'autres protéines, comme les intégrines α6β4 et α3β1, ou les protéoglycanes héparanes sulfates [9,10] La nétrine-1, un ligand des récepteurs à dépendance Les récepteurs DCC et UNC5A, -B et -C, sur lesquels se fixe la nétrine-1, ont été décrits comme les prototypes des récepteurs à dépendance, des protéines membres d'une famille à double fonctionnalité, dont un tout dernier membre, c-kit, a récemment été décrit [11]. En présence de leurs ligands, ces récepteurs induisent un signal dit « positif » qui conduit la cellule à proliférer ou à migrer. ...
La nétrine-1, une molécule sécrétée mise en évidence pour son rôle de guidage au cours de l’embryogenèse, a été également décrite pour être surexprimée dans de nombreux cancers agressifs. Elle est le ligand de récepteurs dits « à dépendance », à l’origine, chez l’adulte, de la survie, de la prolifération et de la migration de différents types cellulaires, ce qui confère aux cellules cancéreuses des propriétés avantageuses leur permettant de se développer sous forme de tumeurs agressives. Une stratégie thérapeutique consiste à inhiber l’interaction de la nétrine-1 avec son récepteur, ce qui déclenche la mort des cellules par apoptose. Cet article présente une revue des caractéristiques fonctionnelles de cette molécule et les effets potentiels d’une nouvelle thérapie ciblée sur la nétrine-1, dont la combinaison avec les traitements conventionnels pourrait être des plus prometteurs.
... Netrin-1 is involved in the migration of GABAergic interneurons. In the developing mouse, netrin-1 is highly expressed in the VZ of the ganglionic eminence and expressed at a lower level in the marginal zone and intermediate zone of the cerebral cortex at the mid-to late-gestational stage (Hamasaki et al., 2001;Stanco et al., 2009). Hamasaki et al. (2001) showed that netrin-1 repels postmitotic GABAergic neurons from the ganglionic eminence. ...
... Mice with genetic deletion of netrin-1, as well as triple-knockouts for Slit1 and Slit2 (expressed in the subpallium) in addition to netrin-1, exhibit a normal distribution of cortical interneurons at E18 (Marin et al., 2003). Nevertheless, Stanco et al. (2009) found that netrin-1 in the marginal zone and intermediate zone guides tangential migration of ganglionic eminence-derived interneurons, which is mediated by α3β1integrin (Figure 2A). In vivo analysis of interneuron-specific α3β1-integrinand netrin-1-deficient mice revealed abnormal interneuron migration along the top of the developing cortical plate, disrupting the distribution of interneurons throughout the cerebral cortex including the hippocampus. ...
In mammals, excitatory cortical neurons develop from the proliferative epithelium and progenitor cells in the ventricular zone and subventricular zone, and migrate radially to the cortical plate, whereas inhibitory GABAergic interneurons are born in the ganglionic eminence and migrate tangentially. The migration of newly born cortical neurons is tightly regulated by both extracellular and intracellular signaling to ensure proper positioning and projections. Non-cell-autonomous extracellular molecules, such as growth factors, axon guidance molecules, extracellular matrix, and other ligands, play a role in cortical migration, either by acting as attractants or repellents. In this article, we review the guidance molecules that act as cell–cell recognition molecules for the regulation of neuronal migration, with a focus on netrin family proteins, their receptors, and related molecules, including neogenin, repulsive guidance molecules (RGMs), Down syndrome cell adhesion molecule (DSCAM), fibronectin leucine-rich repeat transmembrane proteins (FLRTs), and draxin. Netrin proteins induce attractive and repulsive signals depending on their receptors. For example, binding of netrin-1 to deleted in colorectal cancer (DCC), possibly together with Unc5, repels migrating GABAergic neurons from the ventricular zone of the ganglionic eminence, whereas binding to α3β1 integrin promotes cortical interneuron migration. Human genetic disorders associated with these and related guidance molecules, such as congenital mirror movements, schizophrenia, and bipolar disorder, are also discussed.
... To determine the mechanism underlying NTN1/ NEO1-dependent cell migration, we evaluated if these proteins form a complex with integrin-β1 and therefore, a supramolecular structure. NTN1 is known to associate with integrin-β1 in interneurons, promoting cell migration [27], although it cannot be excluded from the possibility that NEO1 is involved in this process. To this end, the association between NEO1, NTN1, and integrin β1, was assessed in coimmunoprecipitation assays in SK-N-SH cells, upon treatment with rhNTN1 (100 ng/ml) for 1 h. ...
Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin β1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin β1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin β1 and promotes neuroblastoma cell migration.
... Aligned with their importance are studies showing that loss of Cxcl12, Cxcr4, or Cxcr7 in vivo impairs intracortical interneuron migration (Tiveron et al., 2006;Li et al., 2008;Sánchez-Alcañiz et al., 2011;Wang et al., 2011b). On the other hand, Netrin attracts interneurons migrating specifically within the marginal zone migratory stream (Stanco et al., 2009). This combination of attractive and repulsive cues facilitates the tangential migration of neurons from their birthplaces in the ventral telencephalon to their final locations in the cortex. ...
Poly (ADP-ribose) polymerase 1 (PARP1) is a ubiquitously expressed enzyme that post-translationally modifies proteins via poly (ADP-ribosylation) (PARylation). PARP1 serves various functions, including DNA damage repair, regulation of cell death pathways, chromatin modification, RNA processing, and transcriptional regulation. Accordingly, mutations in Parp1 or Adprhl2 (encoding the protein ADP-ribosylhydrolase 3, which removes PAR polymers) cause intellectual disability, ataxia, episodic psychosis, neurodegeneration, and developmental delay. Altered PARP1 expression is also associated with numerous neurodegenerative and neuroimmune disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, rheumatoid arthritis, major depressive disorder, and epilepsy. Despite ubiquitous expression and an apparent connection with brain disorders, PARP1's role in neurodevelopment has not been widely studied. Our lab has recently uncovered a novel interaction between PARP1 and the receptor tyrosine kinase ErbB4, which binds its ligand NRG1 to mediate numerous functions during neurodevelopment, including radial migration of excitatory neurons, tangential migration of inhibitory neurons, synaptogenesis, and differentiation. Additionally, ErbB4 has multiple splice forms that confer different signaling modalities. Specifically, the ErbB4-juxtamembrane (JM)-a isoform is cleavable via the enzymes tumor necrosis factor-alpha (TACE) and presenilin/gamma-secretase. Upon NRG1 binding and ErbB4-JMa cleavage, the ErbB4 intracellular domain (E4ICD) is released, which regulates transcription through direct promoter binding. Previous findings have shown that E4ICD complexes with co-factors to repress gliogenesis during early development. Due to PARP1's prominent roles in chromatin modification and transcriptional control, this begs the question as to whether PARP1 is likewise regulating glial gene expression via E4ICD. The aims of this dissertation are two-fold: 1) investigate the role of PARP1 in regulating astrocytic gene expression via E4ICD and 2) further characterize the effect of PARP1 loss on brain development. To explore the role of PARP1-E4ICD in the regulation of astrogenesis, I utilized mouse primary embryonic neural precursor cell (NPC) cultures and transgenic mice with a germline knockout of PARP1, ErbB4, or ErbB4-JMa. I found that NRG1-mediated repression of GFAP expression upon FGF removal from NPC cultures was dependent upon the presence of PARP1, ErbB4, and ErbB4-JMa. Additionally, I showed that PARP1 KO and ErbB4 KO mice overexpress GFAP at birth, indicating the importance of both proteins in vivo. To investigate the effect of PARP1 loss on neurodevelopment more broadly, I analyzed the brain and cortical size of PARP1 KO mice at birth, finding a reduction in brain weight relative to body size, which is associated with a thinner cortex and a reduced cortical surface area. Furthermore, I discovered that PARP1 loss alters early-born neuron migration and increases the density of deeper-layer neurons. To investigate changes in gene expression associated with these findings, I performed RNA-sequencing of the embryonic PARP1 KO cortex. I found that PARP1 loss increases the expression of genes involved in neuronal migration and adhesion, including Reln, which encodes the glycoprotein Reelin. Accordingly, my findings indicate that PARP1 loss increases the abundance of Reelin-expressing cells in the developing (E15.5) and adolescent (P5) mouse brain. I further demonstrated that PARP1 loss, inhibition, or acute knockdown increases Cajal-Retzius cell abundance in vitro, suggesting PARP1 regulates Cajal-Retzius cell development via a cell-autonomous mechanism. Finally, atomic force microscopy showed that NPCs isolated from the PARP1 KO cortex adhere more strongly to the cell adhesion molecule N-cadherin, likely due to excess Reelin. Overall, these findings demonstrate that PARP1 regulates astrogenesis, Cajal-Retzius cell development, and cell adhesion in the developing brain.
... The N-terminal domains of netrins consist of three epidermal growth factorlike repeats, similar to the laminin gamma chain, whereas their C-terminal domains are not homologous to laminins (Kappler et al., 2000). Netrin-1 regulates axon guidance as both attractive and repulsive cues by binding to Unc5 family proteins, deleted in colorectal carcinoma (DCC), neogenin, down syndrome cell adhesion molecule (DSCAM), and integrin family proteins in vertebrates (Arakawa, 2004;Ly et al., 2008;Stanco et al., 2009;Adams and Eichmann, 2010;Castets and Mehlen, 2010;Dun and Parkinson, 2017). Netrin-1 also modulates oligodendrogenesis in various regions. ...
In the adult mouse brain, neurogenesis occurs mainly in the ventricular-subventricular zone (V-SVZ) and the subgranular zone of the hippocampal dentate gyrus. Neuroblasts generated in the V-SVZ migrate to the olfactory bulb via the rostral migratory stream (RMS) in response to guidance molecules, such as netrin-1. We previously showed that the related netrin-5 (NTN5) is expressed in Mash1-positive transit-amplifying cells and doublecortin-positive neuroblasts in the granule cell layer of the olfactory bulb, the RMS, and the subgranular zone of the adult mouse brain. However, the precise role of NTN5 in adult neurogenesis has not been investigated. In this study, we show that proliferation in the neurogenic niche is impaired in NTN5 knockout mice. The number of proliferating (EdU-labeled) cells in NTN5 KO mice was significantly lower in the V-SVZ, whereas the number of Ki67-positive proliferating cells was unchanged, suggesting a longer cell cycle and decreased cell division in NTN5 KO mice. The number of EdU-labeled cells in the RMS and olfactory bulb was unchanged. By contrast, the numbers of EdU-labeled cells in the cortex, basal ganglia/lateral septal nucleus, and corpus callosum/anterior commissure were increased, which largely represented oligodendrocyte lineage cells. Lastly, we found that chain migration in the RMS of NTN5 KO mice was disorganized. These findings suggest that NTN5 may play important roles in promoting proliferation in the V-SVZ niche, organizing proper chain migration in the RMS, and suppressing oligodendrogenesis in the brain.
... Netrin-1 sinyal etkisini, UNC5A-D veya UNC5H1-4, down sendromu hücre adhezyon molekülü (DSCAM), integrin α3β1 ve α6β3, serebellin 4 (CBLN4) içeren dört ilave reseptörün yanı sıra reseptör olup olmadığı net olarak açıklığa kavuşturulamamış olan adenozin reseptörü (A2bR) aracılığıyla gösterir(Şekil 2) [11][12][13][14][15][16][17][18][19] . ...
Laminin benzeri proteinlerin bir ailesi olan netrinler, başlangıçta embriyonik aksonal rehberlikteki rolleri ile tanımlanmıştır. Kemotropik özellik gösteren bu moleküller nöron göçünün iki fonksiyonlu bir düzenleyicisi gibi davranırlar. Araştırmacılar, merkezi sinir sistemindeki rolünden bağımsız olarak netrin-1'in sinir haricindeki dokuların gelişiminde ve oluşumunda rol oynadığını kanıtlamıştırKardiyovasküler alanla ilgili olarak, netrin-1 anjiyogenezi teşvik eder ve aterosklerozu hızlandırır, kalbi iskemi-reperfüzyon hasarına karşı korur ve infarktüs boyutunu azaltır.Bu bulgular, özellikle birçok fizyolojik ve patofizyolojik süreçte birbiriyle çelişebilen etkileri olduğu için netrin-1’i önemli bir terapötik hedef haline getirmektedir. Bu derlemede ateroskleroz, anjiyojenez ve iskemi reperfüzyon onarımı da dahil olmak üzere kardiyovasküler hastalıklar sırasında netrin-1 sinyallerinin işlevleri gözden geçirilmiştir.
... Netrin-1 can bind and activate some of the integrin receptors, including α6β4 and α3β1 (Yebra et al., 2003). These interactions have been shown to mediate epithelial cell adhesion, cell migration, axon guidance, and protection from apoptosis following hypoxia (Lemons et al., 2013;Stanco et al., 2009;Yebra et al., 2003). So far, it is the only netrin-1-receptor interaction known to require the C-domain of netrin-1 (Yebra et al., 2003). ...
The secreted protein netrin-1 has diverse functions among which guidance and survival of neurons when bound to its dependence receptor DCC. In the absence of netrin-1, DCC is cleaved and actively triggers cell death in various contexts. DCC is highly present in a subset of mature neurons that typically degenerates in Parkinson’s disease, dopaminergic neurons of the substantia nigra. Besides, polymorphisms of DCC gene are associated with the disease. Thus, netrin-1 signalling might be implicated in Parkinson’s disease pathogenesis. Here we show, in various Parkinson’s disease models and samples from Parkinson’s disease patient brains, a reduction of netrin-1 levels associated with an increase of DCC cleavage and caspase activity. Specific deletion of netrin-1 in the substantia nigra induces DCC cleavage and leads to the loss of dopamine neurons and motor deficits in mice while intrastriatal injection of netrin-1 restores dopamine neurons and improves motor behaviour in rodent models of the disease. These results highlight the therapeutic potential of targeting netrin-1 signalling in Parkinson’s disease
