scholarly journals Gut regulates brain synaptic assembly through neuroendocrine signaling pathway

2021 ◽  
Author(s):  
Yanjun Shi ◽  
Lu Qin ◽  
Zhiyong Shao
Keyword(s):  
Neuronal Activity ◽  
Neural Development ◽  
Neurological Disorders ◽  
Essential Role ◽  
Neuronal Development ◽  
Genetic Screen ◽  
Synaptic Development ◽  
C Elegans ◽  
Canonical Wnt ◽  
Presynaptic Assembly

AbstractThe gut-brain axis plays an essential role in regulating neural development in response to external environmental stimuli, such as microbes or nutrient availability. Defects in gut-brain communication usually lead to various neurological disorders. However, it remains unknown whether gut plays any intrinsic role in regulating neuronal development. Through a genetic screen in C. elegans, we uncovered that an intrinsic Wnt-endocrine pathway in gut regulates synaptic development and neuronal activity in brain. Specifically, the gut expressed neuropeptide NLP-40 upregulated by a canonical Wnt signaling, which then facilitates presynaptic assembly through regulating GPCR AEX-2 mediated neuronal spontaneous activity. Therefore, this study not only uncovers a novel synaptic development mechanism, but also reveals a novel gut-brain interaction.

scholarly journals Wnt-5a Promotes Neural Development and Differentiation by Regulating CDK5 via Ca2+/Calpain Pathway

2018 ◽  
Vol 51 (6) ◽  
pp. 2604-2615 ◽  
Author(s):  
Yang Shu ◽  
Min Xiang ◽  
Pei Zhang ◽  
Guangjian Qi ◽  
Feng He ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Wnt Signaling ◽  
Neural Development ◽  
Kinase Activity ◽  
Neuronal Development ◽  
Cell Model ◽  
Wnt Signaling Pathway ◽  
Specific Chemical ◽  
Development And Differentiation ◽  
Canonical Wnt

Background/Aims: The Wnt signaling pathway has essential functions in the central nervous system, where it regulates the major physiological functions of neurons, including development, differentiation, and plasticity. Wnt signaling controls these cellular events; however, how Wnt pathways integrate into a coherent developmental program remains unclear. Methods: The expression and secretion of different WNT ligands (Wnt-1, Wnt-3a, Wnt-4, Wnt-5a, Wnt-11), and the levels and activities of cyclin-dependent kinases (CDK2, CDK4, CDK6/cyclin D, cyclin E) or CDK5 (CDK5/p35 and p25) were measured in Rat cortex at different embryonic stages, and in RA/BDNF-induced differentiated SH-SY5Y cell model, by Quantitative real-time PCR (qPCR), western blotting, ELISA, and in vitro CDK5 kinase assays. MAP2-BrdU double staining was used to assess cell differentiation and cell cycle exit in an RA/BDNF-induced differentiated SH-SY5Y cell model. The effects of CDK5 and Ca2+/calpain signaling were assessed using specific chemical inhibitors. Results: We found that Wnt-1 was unchanged and Wnt-3a was attenuated, whereas Wnt-4, Wnt-5a, and Wnt-11 were markedly up-regulated, during the development of neurons and differentiated SH-SY5Y cells. Simultaneously, the activity of CDK5 was elevated. Furthermore, we describe crosstalk between non-canonical Wnt signaling and CDK5 in the development of neurons and differentiated SH-SY5Y cells. Wnt-5a, a non-canonical Wnt ligand, regulated CDK5 via Ca2+/calpain signaling in both neuronal development and differentiation. Inhibition of Wnt-5a diminished CDK5 kinase activity via the Ca2+/calpain pathway, thereby attenuating RA-BDNF induced SH-SY5Y cell differentiation. Conclusion: Wnt-5a signaling is a significant regulator of neuronal development and differentiation and upregulates CDK5 kinase activity via Ca2+/calpain signaling.

scholarly journals KIF1A/UNC-104 transports ATG-9 to regulate neurodevelopment and autophagy at synapses

2016 ◽  
Author(s):  
Andrea K. H. Stavoe ◽  
Sarah E. Hill ◽  
Daniel A. Colón-Ramos
Keyword(s):  
Synaptic Vesicle ◽  
Neuronal Development ◽  
Degradation Process ◽  
Axon Outgrowth ◽  
Genetic Screens ◽  
Autophagosome Formation ◽  
C Elegans ◽  
Physiological Importance ◽  
Polarized Cells ◽  
Presynaptic Assembly

SUMMARYAutophagy is a cellular degradation process essential for neuronal development and survival. Neurons are highly polarized cells in which autophagosome biogenesis is spatially compartmentalized. The mechanisms and physiological importance of this spatial compartmentalization of autophagy in the neuronal development of living animals are not well understood. Here we determine that, in C. elegans neurons, autophagosomes form near synapses and are required for neurodevelopment. We first determined, through unbiased genetic screens and systematic genetic analyses, that autophagy is required cell-autonomously for presynaptic assembly and for axon outgrowth dynamics in specific neurons. We observe autophagosomes in the axon near synapses, and this localization depends on the synaptic vesicle kinesin, KIF1A/UNC-104. KIF1A/UNC-104 coordinates localized autophagosome formation by regulating the transport of the integral membrane autophagy protein, ATG-9. Our findings indicate that autophagy is spatially regulated in neurons through the transport of ATG-9 by KIF1A/UNC-104 to regulate neurodevelopment.

scholarly journals The growing topology of the C. elegans connectome

2021 ◽  
Author(s):  
Alec Helm ◽  
Ann S. Blevins ◽  
Danielle S. Bassett
Keyword(s):  
Motor Neurons ◽  
Neural Development ◽  
Algebraic Topology ◽  
Neuronal Development ◽  
Growth Models ◽  
Persistent Homology ◽  
Small World ◽  
Biological Properties ◽  
C Elegans ◽  
Network Analyses

AbstractProbing the developing neural circuitry in Caenorhabditis elegans has enhanced our understanding of nervous systems. The C. elegans connectome, like those of other species, is characterized by a rich club of densely connected neurons embedded within a small-world architecture. This organization of neuronal connections, captured by quantitative network statistics, provides insight into the system’s capacity to perform integrative computations. Yet these network measures are limited in their ability to detect weakly connected motifs, such as topological cavities, that may support the system’s capacity to perform segregated computations. We address this limitation by using persistent homology to track the evolution of topological cavities in the growing C. elegans connectome throughout neural development, and assess the degree to which the growing connec-tome’s topology is resistant to biological noise. We show that the developing connectome topology is both relatively robust to changes in neuron birth times and not captured by similar growth models. Additionally, we quantify the consequence of a neuron’s specific birth time and ask if this metric tracks other biological properties of neurons. Our results suggest that the connectome’s growing topology is a robust feature of the developing con-nectome that is distinct from other network properties, and that the growing topology is particularly sensitive to the exact birth times of a small set of predominantly motor neurons. By utilizing novel measurements that track biological features, we anticipate that our study will be helpful in the construction of more accurate models of neuronal development in C. elegans.Author SummaryNetwork analyses have identified several local and global properties of the C. elegans connectome that are relevant to the organism’s function and its capacity for information processing. Recent work has extended those investigations by focusing on the connectome’s growth, in an effort to uncover potential drivers of connectome formation. Here we investigate connectome growth from the perspective of applied algebraic topology, by tracking both changing and persistent homology. In doing so, we are able to measure the resilience of the growth process to perturbations, and assess spatial variations in that resilience throughout the organism’s body. Our findings provide new insights regarding the development of this simple natural connectome, as we have determined the existence of a robust and topologically simple network feature that is unexplained by the presence of other notable features of the connectome.

scholarly journals Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

2021 ◽  
Vol 22 (5) ◽  
pp. 2659
Author(s):  
Gianluca Costamagna ◽  
Giacomo Pietro Comi ◽  
Stefania Corti
Keyword(s):  
Drug Discovery ◽  
Drug Screening ◽  
Neural Development ◽  
Neurological Disorders ◽  
Large Scale ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Cellular Level ◽  
Complex Data ◽  
Complex Data Sets

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

scholarly journals Rgs4 is a regulator of mTOR activity required for motoneuron axon outgrowth and neuronal development in zebrafish

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Mikdache ◽  
Marie-José Boueid ◽  
Lorijn van der Spek ◽  
Emilie Lesport ◽  
Brigitte Delespierre ◽  
...  
Keyword(s):  
Nervous System ◽  
G Protein ◽  
Neural Development ◽  
Neuronal Development ◽  
Axon Outgrowth ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Loss Of Function ◽  
G Protein Coupled

AbstractThe Regulator of G protein signaling 4 (Rgs4) is a member of the RGS proteins superfamily that modulates the activity of G-protein coupled receptors. It is mainly expressed in the nervous system and is linked to several neuronal signaling pathways; however, its role in neural development in vivo remains inconclusive. Here, we generated and characterized a rgs4 loss of function model (MZrgs4) in zebrafish. MZrgs4 embryos showed motility defects and presented reduced head and eye sizes, reflecting defective motoneurons axon outgrowth and a significant decrease in the number of neurons in the central and peripheral nervous system. Forcing the expression of Rgs4 specifically within motoneurons rescued their early defective outgrowth in MZrgs4 embryos, indicating an autonomous role for Rgs4 in motoneurons. We also analyzed the role of Akt, Erk and mechanistic target of rapamycin (mTOR) signaling cascades and showed a requirement for these pathways in motoneurons axon outgrowth and neuronal development. Drawing on pharmacological and rescue experiments in MZrgs4, we provide evidence that Rgs4 facilitates signaling mediated by Akt, Erk and mTOR in order to drive axon outgrowth in motoneurons and regulate neuronal numbers.

scholarly journals Two functionally distinct Axin-like proteins regulate canonical Wnt signaling in C. elegans

2007 ◽  
Vol 308 (2) ◽  
pp. 438-448 ◽  
Author(s):  
Tony Oosterveen ◽  
Damien Y.M. Coudreuse ◽  
Pei-Tzu Yang ◽  
Elizabeth Fraser ◽  
Joost Bergsma ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Canonical Wnt Signaling ◽  
C Elegans ◽  
Canonical Wnt

scholarly journals Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

2017 ◽  
Vol 2017 ◽  
pp. 1-25 ◽  
Author(s):  
Viviana I. Torres ◽  
Daniela Vallejo ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Central Nervous System ◽  
Neurological Disorders ◽  
Neuronal Development ◽  
Protein Complexes ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Complex Structures ◽  
Disease Phenotype ◽  
The Central Nervous System ◽  
Invertebrate Models

Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.

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