Journal articles on the topic 'CircRNAs, brain wiring, axon'
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Lewis, Tommy L., Julien Courchet, and Franck Polleux. "Cellular and molecular mechanisms underlying axon formation, growth, and branching." Journal of Cell Biology 202, no. 6 (September 16, 2013): 837–48. http://dx.doi.org/10.1083/jcb.201305098.
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Proper brain wiring during development is pivotal for adult brain function. Neurons display a high degree of polarization both morphologically and functionally, and this polarization requires the segregation of mRNA, proteins, and lipids into the axonal or somatodendritic domains. Recent discoveries have provided insight into many aspects of the cell biology of axonal development including axon specification during neuronal polarization, axon growth, and terminal axon branching during synaptogenesis.
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Mason, Carol, and Nefeli Slavi. "Retinal Ganglion Cell Axon Wiring Establishing the Binocular Circuit." Annual Review of Vision Science 6, no. 1 (September 15, 2020): 215–36. http://dx.doi.org/10.1146/annurev-vision-091517-034306.
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Binocular vision depends on retinal ganglion cell (RGC) axon projection either to the same side or to the opposite side of the brain. In this article, we review the molecular mechanisms for decussation of RGC axons, with a focus on axon guidance signaling at the optic chiasm and ipsi- and contralateral axon organization in the optic tract prior to and during targeting. The spatial and temporal features of RGC neurogenesis that give rise to ipsilateral and contralateral identity are described. The albino visual system is highlighted as an apt comparative model for understanding RGC decussation, as albinos have a reduced ipsilateral projection and altered RGC neurogenesis associated with perturbed melanogenesis in the retinal pigment epithelium. Understanding the steps for RGC specification into ipsi- and contralateral subtypes will facilitate differentiation of stem cells into RGCs with proper navigational abilities for effective axon regeneration and correct targeting of higher-order visual centers.
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Wang, Wei, Asit Rai, Eun-Mi Hur, Zeev Smilansky, Karen T. Chang, and Kyung-Tai Min. "DSCR1 is required for both axonal growth cone extension and steering." Journal of Cell Biology 213, no. 4 (May 16, 2016): 451–62. http://dx.doi.org/10.1083/jcb.201510107.
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Local information processing in the growth cone is essential for correct wiring of the nervous system. As an axon navigates through the developing nervous system, the growth cone responds to extrinsic guidance cues by coordinating axon outgrowth with growth cone steering. It has become increasingly clear that axon extension requires proper actin polymerization dynamics, whereas growth cone steering involves local protein synthesis. However, molecular components integrating these two processes have not been identified. Here, we show that Down syndrome critical region 1 protein (DSCR1) controls axon outgrowth by modulating growth cone actin dynamics through regulation of cofilin activity (phospho/dephospho-cofilin). Additionally, DSCR1 mediates brain-derived neurotrophic factor–induced local protein synthesis and growth cone turning. Our study identifies DSCR1 as a key protein that couples axon growth and pathfinding by dually regulating actin dynamics and local protein synthesis.
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Jia, Erteng, Ying Zhou, Zhiyu Liu, Liujing Wang, Tinglan Ouyang, Min Pan, Yunfei Bai, and Qinyu Ge. "Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson’s Disease in a Mouse Model." International Journal of Molecular Sciences 21, no. 8 (April 24, 2020): 3006. http://dx.doi.org/10.3390/ijms21083006.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease and although many studies have been done on this disease, the underlying mechanisms are still poorly understood and further studies are warranted. Therefore, this study identified circRNA expression profiles in the cerebral cortex (CC), hippocampus (HP), striatum (ST), and cerebellum (CB) regions of the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model using RNA sequencing (RNA-seq), and differentially expressed circRNA were validated using reverse transcription quantitative real-time PCR (qRT-PCR). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analyses were also performed to explore the potential function of circRNAs. The results show that, compared with the control group, 24, 66, 71, and 121 differentially expressed circRNAs (DE-circRNAs) were found in the CC, HP, ST, and CB, respectively. PDST vs. PDCB, PDST vs. PDHP, and PDCB vs. PDHP groups have 578, 110, and 749 DE-circRNAs, respectively. Then, seven DE-cirRNAs were selected for qRT-PCR verification, where the expressions were consistent with the sequencing analysis. The GO and KEGG pathway analyses revealed that these DE-circRNAs participate in several biological functions and signaling pathways, including glutamic synapse, neuron to neuron synapse, cell morphogenesis involved in neuron differentiation, Parkinson’s disease, axon guidance, cGMP-PKG signaling pathway, and PI3K-Akt signaling pathway. Furthermore, the KEGG analysis of the target genes predicted by DE-circRNAs indicated that the target genes predicted by mmu_circRNA_0003292, mmu_circRNA_0001320, mmu_circRNA_0005976, and mmu_circRNA_0005388 were involved in the PD-related pathway. Overall, this is the first study on the expression profile of circRNAs in the different brain regions of PD mouse model. These results might facilitate our understanding of the potential roles of circRNAs in the pathogenesis of PD. Moreover, the results also indicate that the mmu_circRNA_0003292-miRNA-132-Nr4a2 pathway might be involved in the regulation of the molecular mechanism of Parkinson’s disease.
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Charron, F. "Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance." Development 132, no. 10 (May 15, 2005): 2251–62. http://dx.doi.org/10.1242/dev.01830.
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Umeda, Kentaro, Nariaki Iwasawa, Manabu Negishi, and Izumi Oinuma. "A short splicing isoform of afadin suppresses the cortical axon branching in a dominant-negative manner." Molecular Biology of the Cell 26, no. 10 (May 15, 2015): 1957–70. http://dx.doi.org/10.1091/mbc.e15-01-0039.
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Precise wiring patterns of axons are among the remarkable features of neuronal circuit formation, and establishment of the proper neuronal network requires control of outgrowth, branching, and guidance of axons. R-Ras is a Ras-family small GTPase that has essential roles in multiple phases of axonal development. We recently identified afadin, an F-actin–binding protein, as an effector of R-Ras mediating axon branching through F-actin reorganization. Afadin comprises two isoforms—l-afadin, having the F-actin–binding domain, and s-afadin, lacking the F-actin–binding domain. Compared with l-afadin, s-afadin, the short splicing variant of l-afadin, contains RA domains but lacks the F-actin–binding domain. Neurons express both isoforms; however, the function of s-afadin in brain remains unknown. Here we identify s-afadin as an endogenous inhibitor of cortical axon branching. In contrast to the abundant and constant expression of l-afadin throughout neuronal development, the expression of s-afadin is relatively low when cortical axons branch actively. Ectopic expression and knockdown of s-afadin suppress and promote branching, respectively. s-Afadin blocks the R-Ras–mediated membrane translocation of l-afadin and axon branching by inhibiting the binding of l-afadin to R-Ras. Thus s-afadin acts as a dominant-negative isoform in R-Ras-afadin–regulated axon branching.
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Rhiner, Christa, and Michael O. Hengartner. "Sugar Antennae for Guidance Signals: Syndecans and Glypicans Integrate Directional Cues for Navigating Neurons." Scientific World JOURNAL 6 (2006): 1024–36. http://dx.doi.org/10.1100/tsw.2006.202.
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Attractive and repulsive signals guide migrating nerve cells in all directions when the nervous system starts to form. The neurons extend thin processes, axons, that connect over wide distances with other brain cells to form a complicated neuronal network. One of the most fascinating questions in neuroscience is how the correct wiring of billions of nerve cells in our brain is controlled. Several protein families are known to serve as guidance cues for navigating neurons and axons. Nevertheless, the combinatorial potential of these proteins seems to be insufficient to sculpt the entire neuronal network and the appropriate formation of connections. Recently, heparan sulfate proteoglycans (HSPGs), which are present on the cell surface of neurons and in the extracellular matrix through which neurons and axons migrate, have been found to play a role in regulating cell migration and axon guidance. Intriguingly, the large number of distinct modifications that can be put onto the sugar side chains of these PGs would in principle allow for an enormous diversity of HSPGs, which could help in regulating the vast number of guidance choices taken by individual neurons. In this review, we will focus on the role of the cell surface HSPGs syndecan and glypican and specific HS modifications in promoting neuronal migration, axon guidance, and synapse formation.
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Moreno Bravo, J. A. "Development of bilateral circuits of the nervous system: From molecular mechanisms to the cerebellum and its implication in neurodevelopmental disorders." ANALES RANM 139, no. 139(03) (2023): 229–35. http://dx.doi.org/10.32440/ar.2022.139.03.rev02.
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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.
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Haber, Suzanne N., Hesheng Liu, Jakob Seidlitz, and Ed Bullmore. "Prefrontal connectomics: from anatomy to human imaging." Neuropsychopharmacology 47, no. 1 (September 28, 2021): 20–40. http://dx.doi.org/10.1038/s41386-021-01156-6.
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AbstractThe fundamental importance of prefrontal cortical connectivity to information processing and, therefore, disorders of cognition, emotion, and behavior has been recognized for decades. Anatomic tracing studies in animals have formed the basis for delineating the direct monosynaptic connectivity, from cells of origin, through axon trajectories, to synaptic terminals. Advances in neuroimaging combined with network science have taken the lead in developing complex wiring diagrams or connectomes of the human brain. A key question is how well these magnetic resonance imaging (MRI)-derived networks and hubs reflect the anatomic “hard wiring” first proposed to underlie the distribution of information for large-scale network interactions. In this review, we address this challenge by focusing on what is known about monosynaptic prefrontal cortical connections in non-human primates and how this compares to MRI-derived measurements of network organization in humans. First, we outline the anatomic cortical connections and pathways for each prefrontal cortex (PFC) region. We then review the available MRI-based techniques for indirectly measuring structural and functional connectivity, and introduce graph theoretical methods for analysis of hubs, modules, and topologically integrative features of the connectome. Finally, we bring these two approaches together, using specific examples, to demonstrate how monosynaptic connections, demonstrated by tract-tracing studies, can directly inform understanding of the composition of PFC nodes and hubs, and the edges or pathways that connect PFC to cortical and subcortical areas.
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Paolino, Annalisa, Laura R. Fenlon, Peter Kozulin, Elizabeth Haines, Jonathan W. C. Lim, Linda J. Richards, and Rodrigo Suárez. "Differential timing of a conserved transcriptional network underlies divergent cortical projection routes across mammalian brain evolution." Proceedings of the National Academy of Sciences 117, no. 19 (April 20, 2020): 10554–64. http://dx.doi.org/10.1073/pnas.1922422117.
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A unique combination of transcription factor expression and projection neuron identity demarcates each layer of the cerebral cortex. During mouse and human cortical development, the transcription factor CTIP2 specifies neurons that project subcerebrally, while SATB2 specifies neuronal projections via the corpus callosum, a large axon tract connecting the two neocortical hemispheres that emerged exclusively in eutherian mammals. Marsupials comprise the sister taxon of eutherians but do not have a corpus callosum; their intercortical commissural neurons instead project via the anterior commissure, similar to egg-laying monotreme mammals. It remains unknown whether divergent transcriptional networks underlie these cortical wiring differences. Here, we combine birth-dating analysis, retrograde tracing, gene overexpression and knockdown, and axonal quantification to compare the functions of CTIP2 and SATB2 in neocortical development, between the eutherian mouse and the marsupial fat-tailed dunnart. We demonstrate a striking degree of structural and functional homology, whereby CTIP2 or SATB2 of either species is sufficient to promote a subcerebral or commissural fate, respectively. Remarkably, we reveal a substantial delay in the onset of developmental SATB2 expression in mice as compared to the equivalent stage in dunnarts, with premature SATB2 overexpression in mice to match that of dunnarts resulting in a marsupial-like projection fate via the anterior commissure. Our results suggest that small alterations in the timing of regulatory gene expression may underlie interspecies differences in neuronal projection fate specification.
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Shibata, Fumi, Yuko Goto-Koshino, Miyuki Ito, Yumi Fukuchi, Yoshihiro Morikawa, Hiromichi Matsushita, Hayato Miyachi, Toshio Kitamura, and Hideaki Nakajima. "Robo4/Magic Roundabout Is a Novel Surface Marker for Murine and Human Hematopoietic Stem Cells." Blood 108, no. 11 (November 16, 2006): 682. http://dx.doi.org/10.1182/blood.v108.11.682.682.
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Abstract A variety of cell surface markers such as c-Kit, Sca-1, CD34 and Flt-3 have been utilized to prospectively isolate murine or human hematopoietic stem cells (HSCs). While murine HSCs were shown to be highly enriched in CD34−c-Kit+Sca-1+Lineage- (CD34−KSL) fraction, this population is still not homogeneous for long-term HSCs. In human, CD34+ cells are regarded as crude HSC fraction and used for clinical applications. However, quiescent human HSCs are also found in CD34− fraction, indicating that CD34 is not a bona fide marker for human HSC. Thus, novel surface markers that can be used to purify human or murine HSCs to homogeneity need to be identified. Roundabout (Robo) family proteins are immunoglobulin-type cell surface receptors that are predominantly expressed in nervous system. Slit2, a ligand for Robo, is a large leucine-rich repeat-containing secreted protein that is also expressed in brain. By binding with Robo, Slit2 acts as a repellant for axon guidance of developing neurons and they are critical for correct wiring of neuronal network. Robo family comprises four family members, Robo1 – Robo4, and Robo4 is distinct in that it is expressed specifically in endothelial cells, but not in brain. In this study, we investigated Robo4 for its possible application for HSC identification in murine and human hematopoietic system. By RT-PCR, Robo4 was specifically expressed in murine KSL fraction, and was not expressed in lineage positive cells and various progenitors such as common myeloid progenitor (CMP), granulocyte-monocyte progenitor (GMP), megakaryocyte/erythroid progenitor (MEP) and common lymphoid progenitor (CLP). Moreover, the expression of Robo4 was highest in side population of KSL cells (KSL-SP), and moderate in KSL-main population (KSL-MP) cells. Monoclonal antibody raised against Robo4 identified its high expression in KSL cells by FACS. FACS analysis of human cord blood cells revealed that Robo4 is highly expressed in CD34+ cells, and CD34+Robo4high population fell into CD38− fraction, which enriches human HSCs. Bone marrow transplantation experiments revealed that Robo4+ fraction of murine KSL cells had long-term repopulating activity, while Robo4−KSL cells not. Although both Robo4+ and Robo4− CD34−KSL cells repopulated murine hematopoietic system for long-term, Robo4+CD34−KSL cells achieved higher chimerism after repopulation compared with Robo4−CD34−KSL. To investigate the physiological role of Robo4 in HSC homeostasis, we next examined the expression of Slit2 in hematopoietic system. Interestingly, Slit2 is specifically expressed in bone marrow stromal cells, but not in hematopoietic cells. Moreover, Slit2 is induced in osteoblasts, a critical cellular component composing HSC niche, in response to myelosuppressive stress such as 5FU treatment. These results indicate that Robo4 is expressed in murine and human hematopoietic HSCs and useful for HSC purification, and Robo4 - Slit2 system may play a role in HSC physiology in niche environment under hematopoietic stress.
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Xu, Xinli, Rui O. Beleza, Francisco Q. Gonçalves, Sergio Valbuena, Sofia Alçada-Morais, Nélio Gonçalves, Joana Magalhães, et al. "Adenosine A2A receptors control synaptic remodeling in the adult brain." Scientific Reports 12, no. 1 (August 29, 2022). http://dx.doi.org/10.1038/s41598-022-18884-4.
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AbstractThe molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A2A receptors (A2AR) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A2AR to MF sprouting. A2AR blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A2AR located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A2AR to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A2AR should be activated by extracellular ATP-derived adenosine since a similar prevention/attenuation of SE-induced hippocampal MF sprouting was observed in CD73 knockout mice. These findings demonstrate that A2AR contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A2AR to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A2AR axis as a regulator of circuit remodeling in the mature brain.
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Langen, Marion, Marta Koch, Jiekun Yan, Natalie De Geest, Maria-Luise Erfurth, Barret D. Pfeiffer, Dietmar Schmucker, Yves Moreau, and Bassem A. Hassan. "Mutual inhibition among postmitotic neurons regulates robustness of brain wiring in Drosophila." eLife 2 (March 5, 2013). http://dx.doi.org/10.7554/elife.00337.
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Brain connectivity maps display a delicate balance between individual variation and stereotypy, suggesting the existence of dedicated mechanisms that simultaneously permit and limit individual variation. We show that during the development of the Drosophila central nervous system, mutual inhibition among groups of neighboring postmitotic neurons during development regulates the robustness of axon target choice in a nondeterministic neuronal circuit. Specifically, neighboring postmitotic neurons communicate through Notch signaling during axonal targeting, to ensure balanced alternative axon target choices without a corresponding change in cell fate. Loss of Notch in postmitotic neurons modulates an axon's target choice. However, because neighboring axons respond by choosing the complementary target, the stereotyped connectivity pattern is preserved. In contrast, loss of Notch in clones of neighboring postmitotic neurons results in erroneous coinnervation by multiple axons. Our observations establish mutual inhibition of axonal target choice as a robustness mechanism for brain wiring and unveil a novel cell fate independent function for canonical Notch signaling.
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Fassier, Coralie, and Xavier Nicol. "Retinal Axon Interplay for Binocular Mapping." Frontiers in Neural Circuits 15 (June 4, 2021). http://dx.doi.org/10.3389/fncir.2021.679440.
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In most mammals, retinal ganglion cell axons from each retina project to both sides of the brain. The segregation of ipsi and contralateral projections into eye-specific territories in their main brain targets—the dorsolateral geniculate nucleus and the superior colliculus—is critical for the processing of visual information. The investigation of the developmental mechanisms contributing to the wiring of this binocular map in mammals identified competitive mechanisms between axons from each retina while interactions between axons from the same eye were challenging to explore. Studies in vertebrates lacking ipsilateral retinal projections demonstrated that competitive mechanisms also exist between axons from the same eye. The development of a genetic approach enabling the differential manipulation and labeling of neighboring retinal ganglion cells in a single mouse retina revealed that binocular map development does not only rely on axon competition but also involves a cooperative interplay between axons to stabilize their terminal branches. These recent insights into the developmental mechanisms shaping retinal axon connectivity in the brain will be discussed here.
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Moreland, Trevor, and Fabienne E. Poulain. "To Stick or Not to Stick: The Multiple Roles of Cell Adhesion Molecules in Neural Circuit Assembly." Frontiers in Neuroscience 16 (April 28, 2022). http://dx.doi.org/10.3389/fnins.2022.889155.
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Precise wiring of neural circuits is essential for brain connectivity and function. During development, axons respond to diverse cues present in the extracellular matrix or at the surface of other cells to navigate to specific targets, where they establish precise connections with post-synaptic partners. Cell adhesion molecules (CAMs) represent a large group of structurally diverse proteins well known to mediate adhesion for neural circuit assembly. Through their adhesive properties, CAMs act as major regulators of axon navigation, fasciculation, and synapse formation. While the adhesive functions of CAMs have been known for decades, more recent studies have unraveled essential, non-adhesive functions as well. CAMs notably act as guidance cues and modulate guidance signaling pathways for axon pathfinding, initiate contact-mediated repulsion for spatial organization of axonal arbors, and refine neuronal projections during circuit maturation. In this review, we summarize the classical adhesive functions of CAMs in axonal development and further discuss the increasing number of other non-adhesive functions CAMs play in neural circuit assembly.
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Gallo, Nicholas B., Artan Berisha, and Linda Van Aelst. "Microglia regulate chandelier cell axo-axonic synaptogenesis." Proceedings of the National Academy of Sciences 119, no. 11 (March 9, 2022). http://dx.doi.org/10.1073/pnas.2114476119.
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Significance Chandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) of neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance of proper ChC function is further underscored by the association of ChC connectivity defects with various neurological conditions. Despite this, the cellular mechanisms governing ChC axo-axonic synapse formation remain poorly understood. Here, we identify microglia as key regulators of ChC axonal morphogenesis and AIS synaptogenesis, and show that disease-induced aberrant microglial activation perturbs proper ChC synaptic development/connectivity in the neocortex. In doing so, such findings highlight the therapeutic potential of manipulating microglia to ensure proper brain wiring.
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Özel, Mehmet Neset, Marion Langen, Bassem A. Hassan, and P. Robin Hiesinger. "Filopodial dynamics and growth cone stabilization in Drosophila visual circuit development." eLife 4 (October 29, 2015). http://dx.doi.org/10.7554/elife.10721.
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Filopodial dynamics are thought to control growth cone guidance, but the types and roles of growth cone dynamics underlying neural circuit assembly in a living brain are largely unknown. To address this issue, we have developed long-term, continuous, fast and high-resolution imaging of growth cone dynamics from axon growth to synapse formation in cultured Drosophila brains. Using R7 photoreceptor neurons as a model we show that >90% of the growth cone filopodia exhibit fast, stochastic dynamics that persist despite ongoing stepwise layer formation. Correspondingly, R7 growth cones stabilize early and change their final position by passive dislocation. N-Cadherin controls both fast filopodial dynamics and growth cone stabilization. Surprisingly, loss of N-Cadherin causes no primary targeting defects, but destabilizes R7 growth cones to jump between correct and incorrect layers. Hence, growth cone dynamics can influence wiring specificity without a direct role in target recognition and implement simple rules during circuit assembly.
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Wilson, Carlos, Ana Lis Moyano, and Alfredo Cáceres. "Perspectives on Mechanisms Supporting Neuronal Polarity From Small Animals to Humans." Frontiers in Cell and Developmental Biology 10 (April 19, 2022). http://dx.doi.org/10.3389/fcell.2022.878142.
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Axon-dendrite formation is a crucial milestone in the life history of neurons. During this process, historically referred as “the establishment of polarity,” newborn neurons undergo biochemical, morphological and functional transformations to generate the axonal and dendritic domains, which are the basis of neuronal wiring and connectivity. Since the implementation of primary cultures of rat hippocampal neurons by Gary Banker and Max Cowan in 1977, the community of neurobiologists has made significant achievements in decoding signals that trigger axo-dendritic specification. External and internal cues able to switch on/off signaling pathways controlling gene expression, protein stability, the assembly of the polarity complex (i.e., PAR3-PAR6-aPKC), cytoskeleton remodeling and vesicle trafficking contribute to shape the morphology of neurons. Currently, the culture of hippocampal neurons coexists with alternative model systems to study neuronal polarization in several species, from single-cell to whole-organisms. For instance, in vivo approaches using C. elegans and D. melanogaster, as well as in situ imaging in rodents, have refined our knowledge by incorporating new variables in the polarity equation, such as the influence of the tissue, glia-neuron interactions and three-dimensional development. Nowadays, we have the unique opportunity of studying neurons differentiated from human induced pluripotent stem cells (hiPSCs), and test hypotheses previously originated in small animals and propose new ones perhaps specific for humans. Thus, this article will attempt to review critical mechanisms controlling polarization compiled over decades, highlighting points to be considered in new experimental systems, such as hiPSC neurons and human brain organoids.
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Tonazzini, Ilaria, Geeske M. Van Woerden, Cecilia Masciullo, Edwin J. Mientjes, Ype Elgersma, and Marco Cecchini. "The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons." Molecular Autism 10, no. 1 (November 29, 2019). http://dx.doi.org/10.1186/s13229-019-0293-1.
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Abstract Background Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Methods Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. Results We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber–binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype. Conclusions We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity.