scholarly journals Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor Sema 3A

2021 ◽  
Author(s):  
Damaris N Lorenzo ◽  
Blake A Creighton ◽  
Deepa Ajit ◽  
Simone Afriyie ◽  
Julia C Bay
Keyword(s):  
Brain Connectivity ◽  
Autism Spectrum ◽  
Axonal Guidance ◽  
Axon Collateral ◽  
Collateral Branch ◽  
Behavioral Abnormalities ◽  
Neuropilin 1 ◽  
Branch Formation ◽  
Ankyrin B

Variants in the high confident autism spectrum disorder gene ANK2 target both ubiquitously expressed 220-kDa ankyrin- B and neurospecific 440-kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3A (Sema 3A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal guidance and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

scholarly journals Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor sema 3A

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Blake A Creighton ◽  
Simone Afriyie ◽  
Deepa Ajit ◽  
Cristine R Casingal ◽  
Kayleigh M Voos ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Autism Spectrum ◽  
Axon Collateral ◽  
Collateral Branch ◽  
Cellular Assays ◽  
Behavioral Abnormalities ◽  
Neuropilin 1 ◽  
Branch Formation ◽  
Ankyrin B

Variants in the high confident autism spectrum disorder (ASD) gene ANK2 target both ubiquitously expressed 220 kDa ankyrin-B and neurospecific 440 kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD-linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3 A (Sema 3 A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal targeting and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

scholarly journals The role of Neuropilin-1 in COVID-19

2021 ◽  
Vol 17 (1) ◽  
pp. e1009153
Author(s):  
Bindu S. Mayi ◽  
Jillian A. Leibowitz ◽  
Arden T. Woods ◽  
Katherine A. Ammon ◽  
Alphonse E. Liu ◽  
...  
Keyword(s):  
Immune Function ◽  
Viral Entry ◽  
Axonal Guidance ◽  
Cell Surface Receptor ◽  
Neuropilin 1 ◽  
Surface Receptor ◽  
The Central Nervous System

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.

scholarly journals Giant ankyrin-B suppresses stochastic collateral axon branching through direct interaction with microtubules

2020 ◽  
Vol 219 (8) ◽  
Author(s):  
Keyu Chen ◽  
Rui Yang ◽  
Yubing Li ◽  
Jin Chuan Zhou ◽  
Mingjie Zhang
Keyword(s):  
Tandem Repeats ◽  
Direct Interaction ◽  
Binding Activity ◽  
Axon Collateral ◽  
Axon Branching ◽  
Microtubule Binding ◽  
Ankyrin G ◽  
Binding Avidity ◽  
Ankyrin B

Giant ankyrin-B (gAnkB) is a 440-kD neurospecific ankyrin-B isoform and a high-confidence target for autism mutations. gAnkB suppresses axon branching through coordination of cortical microtubules, and autism-related mutation of gAnkB results in ectopic neuronal connectivity. We identified a bipartite motif from gAnkB, which bundles and avidly binds to microtubules in vitro. This motif is composed of a module of 15 tandem repeats followed by a short, conserved fragment also found in giant ankyrin-G (BG-box). Combination of these two parts synergistically increases microtubule-binding avidity. Transfection of astrocytes (which lack gAnkB) with WT gAnkB resulted in prominent bundling of microtubules, which did not occur with mutant gAnkB with impaired microtubule-binding activity. Similarly, rescue of gAnkB-deficient neurons with WT gAnkB suppressed axonal branching and invasion of EB3-tagged microtubules into filopodia, which did not occur with the same mutant gAnkB. Together, these findings demonstrate that gAnkB suppresses axon collateral branching and prevents microtubule invasion of nascent axon branches through direct interaction with microtubules.

Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 5043-5053 ◽  
Author(s):  
D. Bagnard ◽  
M. Lohrum ◽  
D. Uziel ◽  
A.W. Puschel ◽  
J. Bolz
Keyword(s):  
Cortical Neurons ◽  
Specific Binding ◽  
Ventricular Zone ◽  
Growth Cones ◽  
Axonal Guidance ◽  
Class Iii ◽  
Neuropilin 1 ◽  
Essential Components

Members of the semaphorin family have been implicated in mediating axonal guidance in the nervous system by their ability to collapse growth cones and to function as chemorepellents. The present findings show that recombinant Semaphorin D has similar effects on cortical axons and, in addition, inhibits axonal branching. In contrast, semaphorin E acts as an attractive guidance signal for cortical axons. Attractive effects were only observed when growth cones encountered increasing concentrations or a patterned distribution of Semaphorin E, but not when they are exposed to uniform concentrations of this molecule. Specific binding sites for Semaphorin D and Semaphorin E were present on cortical fibers both in vitro and in vivo at the time when corticofugal projections are established. In situ hybridization analysis revealed that the population of cortical neurons used in our experiments express neuropilin-1 and neuropilin-2, which are essential components of receptors for the class III semaphorins. Moreover, semD mRNA was detected in the ventricular zone of the neocortex whereas semE mRNA was restricted to the subventricular zone. Taken together, these results indicate that semaphorins are bifunctional molecules whose effects depend on their spatial distribution. The coordinated expression of different semaphorins, together with their specific activities on cortical axons, suggests that multiple guidance signals contribute to the formation of precise corticofugal pathways.

Investigations on the Brain Connectivity Parameters for Co-Morbidities of Autism Using EEG

2018 ◽  
Vol 10 (2) ◽  
pp. 50-65 ◽  
Author(s):  
Vishnu Priya K. ◽  
Kavitha A.
Keyword(s):  
Brain Connectivity ◽  
Autism Spectrum ◽  
Autistic Children ◽  
Eeg Signals ◽  
Biomarker Identification ◽  
Stable Pattern ◽  
Behavioral Abnormalities ◽  
The Brain ◽  
Potential Biomarkers ◽  
Morbid Conditions

This article describes how the Autism Spectrum Disorder (ASD) is a collection of heterogeneous disorders with prevalent cognitive and behavioral abnormalities. ASD is generally considered a life-long disability occurring as a stand-alone disorder but it occurs with possible co-morbid conditions. Electroencephalography (EEG) studies have been identified as one of the most widely used tool for assessing the cognitive functions with strong evidences of stable pattern of EEG associated with ASD. With the understanding of the co-morbidities and the pathophysiology, it needs an appropriate signal processing routine. Hence, this article focuses on the electrophysiological biomarker identification from the acquired EEG signals of low-functioning autistic children to distinguish between the various co-morbidities of autism. Results show that the power, coherence and brain connectivity estimators determined from EEG can be potential biomarkers. The identified biomarkers can thus act as supportive tools for the physician in clinically assessments of Autistic children with difference co-morbidities who differ widely.

scholarly journals A giant ankyrin-B mechanism for neuro-diversity/divergence through stochastic ectopic axon projections

2018 ◽  
Author(s):  
Rui Yang ◽  
Kathryn K. Walder-Christensen ◽  
Namsoo Kim ◽  
Danwei Wu ◽  
Damaris Lorenzo ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Structural Connectivity ◽  
Autism Spectrum ◽  
Membrane Domains ◽  
Social Deficits ◽  
Loss Of Function ◽  
High Confidence ◽  
Microtubule Stabilization ◽  
Wide Range ◽  
Ankyrin B

ABSTRACTANK2 is a high-confidence autism spectrum disorder (ASD) gene where affected individuals exhibit diverse symptoms with a wide range of IQ. We report a cellular mechanism resulting in stochastic brain connectivity that provides a rationale for both gain and loss of function due to ANK2 mutation. Deficiency of giant ankyrin-B (ankB), the neurospecific ANK2 mutation target, results in ectopic CNS axon tracts associated with increased axonal branching. We elucidate a mechanism limiting axon branching, whereby giant ankB is recruited by L1CAM to periodic axonal plasma membrane domains where it coordinates cortical microtubules and prevents microtubule stabilization of nascent axon branches. Heterozygous giant ankB mutant mice exhibit innate social deficits combined with normal/enhanced cognitive function. Thus, giant ankB-deficiency results in gain of aberrant structural connectivity with penetrant behavioral consequences that may contribute to both high and low-function ASD and other forms of neurodiversity/divergence.

Influence of Primary Auditory Cortex in the Characterization of Autism Spectrum in Young Adults using Brain Connectivity Parameters and Deep Belief Networks: An fMRI Study

2020 ◽  
Vol 16 (9) ◽  
pp. 1059-1073
Author(s):  
Vidhusha Srinivasan ◽  
N. Udayakumar ◽  
Kavitha Anandan
Keyword(s):  
Functional Connectivity ◽  
Auditory Cortex ◽  
Language Processing ◽  
Brain Connectivity ◽  
Primary Auditory Cortex ◽  
Autism Spectrum ◽  
Belief Networks ◽  
Deep Belief Networks ◽  
High Functioning ◽  
Low Functioning

Background: The spectrum of autism encompasses High Functioning Autism (HFA) and Low Functioning Autism (LFA). Brain mapping studies have revealed that autism individuals have overlaps in brain behavioural characteristics. Generally, high functioning individuals are known to exhibit higher intelligence and better language processing abilities. However, specific mechanisms associated with their functional capabilities are still under research. Objective: This work addresses the overlapping phenomenon present in autism spectrum through functional connectivity patterns along with brain connectivity parameters and distinguishes the classes using deep belief networks. Methods: The task-based functional Magnetic Resonance Images (fMRI) of both high and low functioning autistic groups were acquired from ABIDE database, for 58 low functioning against 43 high functioning individuals while they were involved in a defined language processing task. The language processing regions of the brain, along with Default Mode Network (DMN) have been considered for the analysis. The functional connectivity maps have been plotted through graph theory procedures. Brain connectivity parameters such as Granger Causality (GC) and Phase Slope Index (PSI) have been calculated for the individual groups. These parameters have been fed to Deep Belief Networks (DBN) to classify the subjects under consideration as either LFA or HFA. Results: Results showed increased functional connectivity in high functioning subjects. It was found that the additional interaction of the Primary Auditory Cortex lying in the temporal lobe, with other regions of interest complimented their enhanced connectivity. Results were validated using DBN measuring the classification accuracy of 85.85% for high functioning and 81.71% for the low functioning group. Conclusion: Since it is known that autism involves enhanced, but imbalanced components of intelligence, the reason behind the supremacy of high functioning group in language processing and region responsible for enhanced connectivity has been recognized. Therefore, this work that suggests the effect of Primary Auditory Cortex in characterizing the dominance of language processing in high functioning young adults seems to be highly significant in discriminating different groups in autism spectrum.

Spastin Interacts with CRMP2 to Regulate Neurite Outgrowth by Controlling Microtubule Dynamics through Phosphorylation Modifications

2020 ◽  
Vol 19 ◽  
Author(s):  
Sumei Li ◽  
Jifeng Zhang ◽  
Jiaqi Zhang ◽  
Jiong Li ◽  
Longfei Cheng ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Hippocampal Neurons ◽  
Neuronal Development ◽  
Phosphorylation Site ◽  
Microtubule Dynamics ◽  
Microtubule Assembly ◽  
C Terminus ◽  
Mediator Protein ◽  
Branch Formation

Aims: Our work aims to revealing the underlying microtubule mechanism of neurites outgrowth during neuronal development, and also proposes a feasible intervention pathway for reconstructing neural network connections after nerve injury. Background: Microtubule polymerization and severing are the basis for the neurite outgrowth and branch formation. Collapsin response mediator protein 2 (CRMP2) regulates axonal growth and branching as a binding partner of the tubulin heterodimer to promote microtubule assembly. And spastin participates in the growth and regeneration of neurites by severing microtubules into small segments. However, how CRMP2 and spastin cooperate to regulate neurite outgrowth by controlling the microtubule dynamics needs to be elucidated. Objective: To explore whether neurite outgrowth was mediated by coordination of CRMP2 and spastin. Method: Hippocampal neurons were cultured in vitro in 24-well culture plates for 4 days before being used to perform the transfection. Calcium phosphate was used to transfect the CRMP2 and spastin constructs and their control into the neurons. An interaction between CRMP2 and spastin was examined by using pull down, CoIP and immunofluorescence colocalization assays. And immunostaining was also performed to determine the morphology of neurites. Result: We first demonstrated that CRMP2 interacted with spastin to promote the neurite outgrowth and branch formation. Furthermore, our results identified that phosphorylation modification failed to alter the binding affinities of CRMP2 for spastin, but inhibited their binding to microtubules. CRMP2 interacted with the MTBD domain of spastin via its C-terminus, and blocking the binding sites of them inhibited the outgrowth and branch formation of neurites. In addition, we confirmed one phosphorylation site S210 at spastin in hippocampal neurons and phosphorylation spastin at site S210 promoted the neurite outgrowth but not branch formation by remodeling microtubules. Conclusion: Taken together, our data demonstrated that the interaction of CRMP2 and spastin is required for neurite outgrowth and branch formation and their interaction is not regulated by their phosphorylation.

scholarly journals Application of Airy beam light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dwaipayan Adhya ◽  
George Chennell ◽  
James A. Crowe ◽  
Eva P. Valencia-Alarcón ◽  
James Seyforth ◽  
...  
Keyword(s):  
High Resolution ◽  
Human Brain ◽  
Light Sheet ◽  
Autism Spectrum ◽  
Model Systems ◽  
Large Field ◽  
Autism Spectrum Conditions ◽  
Patient Specific ◽  
Airy Beam

Abstract Background The inability to observe relevant biological processes in vivo significantly restricts human neurodevelopmental research. Advances in appropriate in vitro model systems, including patient-specific human brain organoids and human cortical spheroids (hCSs), offer a pragmatic solution to this issue. In particular, hCSs are an accessible method for generating homogenous organoids of dorsal telencephalic fate, which recapitulate key aspects of human corticogenesis, including the formation of neural rosettes—in vitro correlates of the neural tube. These neurogenic niches give rise to neural progenitors that subsequently differentiate into neurons. Studies differentiating induced pluripotent stem cells (hiPSCs) in 2D have linked atypical formation of neural rosettes with neurodevelopmental disorders such as autism spectrum conditions. Thus far, however, conventional methods of tissue preparation in this field limit the ability to image these structures in three-dimensions within intact hCS or other 3D preparations. To overcome this limitation, we have sought to optimise a methodological approach to process hCSs to maximise the utility of a novel Airy-beam light sheet microscope (ALSM) to acquire high resolution volumetric images of internal structures within hCS representative of early developmental time points. Results Conventional approaches to imaging hCS by confocal microscopy were limited in their ability to image effectively into intact spheroids. Conversely, volumetric acquisition by ALSM offered superior imaging through intact, non-clarified, in vitro tissues, in both speed and resolution when compared to conventional confocal imaging systems. Furthermore, optimised immunohistochemistry and optical clearing of hCSs afforded improved imaging at depth. This permitted visualization of the morphology of the inner lumen of neural rosettes. Conclusion We present an optimized methodology that takes advantage of an ALSM system that can rapidly image intact 3D brain organoids at high resolution while retaining a large field of view. This imaging modality can be applied to both non-cleared and cleared in vitro human brain spheroids derived from hiPSCs for precise examination of their internal 3D structures. This process represents a rapid, highly efficient method to examine and quantify in 3D the formation of key structures required for the coordination of neurodevelopmental processes in both health and disease states. We posit that this approach would facilitate investigation of human neurodevelopmental processes in vitro.

scholarly journals The Effects of Maternal Interleukin-17A on Social Behavior, Cognitive Function, and Depression-Like Behavior in Mice with Altered Kynurenine Metabolites

2021 ◽  
Vol 14 ◽  
pp. 117864692110266
Author(s):  
Yuki Murakami ◽  
Yukio Imamura ◽  
Yoshiyuki Kasahara ◽  
Chihiro Yoshida ◽  
Yuta Momono ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Maternal Serum ◽  
Fetal Plasma ◽  
Maternal Inflammation ◽  
Interleukin 17A ◽  
Behavioral Abnormalities ◽  
Neuroactive Compounds ◽  
The Impact

Viral infection and chronic maternal inflammation during pregnancy are correlated with a higher prevalence of autism spectrum disorder (ASD). However, the pathoetiology of ASD is not fully understood; moreover, the key molecules that can cross the placenta following maternal inflammation and contribute to the development of ASD have not been identified. Recently, the pro-inflammatory cytokine, interleukin-17A (IL-17A) was identified as a potential mediator of these effects. To investigate the impact of maternal IL-17A on offspring, C57BL/6J dams were injected with IL-17A-expressing plasmids via the tail vein on embryonic day 12.5 (E12.5), and maternal IL-17A was expressed continuously throughout pregnancy. By adulthood, IL-17A-injected offspring exhibited behavioral abnormalities, including social and cognitive defects. Additionally, maternal IL-17A promoted metabolism of the essential amino acid tryptophan, which produces several neuroactive compounds and may affect fetal neurodevelopment. We observed significantly increased levels of kynurenine in maternal serum and fetal plasma. Thus, we investigated the effects of high maternal concentration of kynurenine on offspring by continuously administering mouse dams with kynurenine from E12.5 during gestation. Obviously, maternal kynurenine administration rapidly increased kynurenine levels in the fetal plasma and brain, pointing to the ability of kynurenine to cross the placenta and change the KP metabolites which are affected as neuroactive compounds in the fetal brain. Notably, the offspring of kynurenine-injected mice exhibited behavioral abnormalities similar to those observed in offspring of IL-17A-conditioned mice. Several tryptophan metabolites were significantly altered in the prefrontal cortex of the IL-17A-conditioned and kynurenine-injected adult mice, but not in the hippocampus. Even though we cannot exclude the possibility or other molecules being related to ASD pathogenesis and the presence of a much lower degree of pathway activation, our results suggest that increased kynurenine following maternal inflammation may be a key factor in changing the balance of KP metabolites in fetal brain during neuronal development and represents a therapeutic target for inflammation-induced ASD-like phenotypes.

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