scholarly journals The HUSH complex controls brain architecture and protocadherin fidelity

2021 ◽  
Author(s):  
Astrid Hagelkruys ◽  
Marion Horrer ◽  
Jasmin Taubenschmid-Stowers ◽  
Anoop Kavirayani ◽  
Maria Novatchkova ◽  
...  
Keyword(s):  
Nervous System ◽  
Synapse Formation ◽  
Zinc Finger Protein ◽  
Brain Size ◽  
Brain Evolution ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Neuronal Diversity ◽  
Brain Architecture ◽  
And Function

Fine-tuning of neural connectivity is important for cerebral functions and brain evolution. Protocadherins provide barcodes for neuronal identity as well as synapse formation and expansion of protocadherin cluster genes has been linked to advanced cognitive functions. The tightly controlled stochastic and combinatorial expression of the different protocadherin isoforms in individual neurons provides the molecular basis for neuronal diversity, neuronal network complexity and function of the vertebrate brain. How protocadherins are epigenetically controlled has not yet been fully elucidated. Here we show that the HUSH (human silencing hub) complex containing H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and Microrchidia CW-type zinc finger protein 2 (MORC2), critically controls the fidelity of protocadherin expression. MPP8 and MORC2A are highly expressed in the murine brain and exclusively found in neurons. Genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, MPP8 and MORC2A precisely and selectively suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner, thereby affecting synapse formation. Moreover, we demonstrate that individual MPHOSPH8- or MORC2-deficient neurons in human cerebral organoids express increased numbers of clustered protocadherin isoforms. Our data identify the HUSH complex, previously linked to silencing of repetitive transposable elements, as a key epigenetic regulator of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.

scholarly journals A developmental framework linking neurogenesis and circuit formation in the Drosophila CNS

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Brandon Mark ◽  
Sen-Lin Lai ◽  
Aref Arzan Zarin ◽  
Laurina Manning ◽  
Heather Q Pollington ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Circuit ◽  
Neural Progenitors ◽  
Dependent Manner ◽  
Neuronal Diversity ◽  
Synaptic Targeting ◽  
Connectivity Structure ◽  
Temporal Identity ◽  
And Function ◽  
Circuit Formation

The mechanisms specifying neuronal diversity are well-characterized, yet it remains unclear how or if these mechanisms regulate neural circuit assembly. To address this, we mapped the developmental origin of 160 interneurons from seven bilateral neural progenitors (neuroblasts), and identify them in a synapse-scale TEM reconstruction of the Drosophila larval CNS. We find that lineages concurrently build the sensory and motor neuropils by generating sensory and motor hemilineages in a Notch-dependent manner. Neurons in a hemilineage share common synaptic targeting within the neuropil, which is further refined based on neuronal temporal identity. Connectome analysis shows that hemilineage-temporal cohorts share common connectivity. Finally, we show that proximity alone cannot explain the observed connectivity structure, suggesting hemilineage/temporal identity confers an added layer of specificity. Thus, we demonstrate that the mechanisms specifying neuronal diversity also govern circuit formation and function, and that these principles are broadly applicable throughout the nervous system.

scholarly journals Structure, Expression, and Function of ICAM-5

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Heping Yang
Keyword(s):  
Nervous System ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Synapse Formation ◽  
The Other ◽  
Intercellular Adhesion Molecule ◽  
Cellular Functions ◽  
Binding Partners ◽  
The Central Nervous System ◽  
And Function

Cell adhesion is of utmost importance in normal development and cellular functions. ICAM-5 (intercellular adhesion molecule-5, telencephalin, TLN) is a member of the ICAM family of adhesion proteins. As a novel cell adhesion molecule, ICAM-5 shares many structural similarities with the other members of IgSF, especially the ICAM subgroup; however, ICAM-5 has several unique properties compared to the other ICAMs. With its nine extracellular Ig domains, ICAM-5 is the largest member of ICAM subgroup identified so far. Therefore, it is much more complex than the other ICAMs. The expression of ICAM-5 is confined to the telencephalic neurons of the central nervous system whereas all the other ICAM members are expressed mostly by cells in the immune and blood systems. The developmental appearance of ICAM-5 parallels the time of dendritic elongation and branching, and synapse formation in the telencephalon. As a somatodendrite-specific adhesion molecule, ICAM-5 not only participates in immune-nervous system interactions, it could also participate in neuronal activity, Dendrites’ targeting signals, and cognition. It would not be surprising if future investigations reveal more binding partners and other related functions of ICAM-5.

scholarly journals Adeno-associated virus (AAV) reduces cortical dendritic complexity in a TLR9-dependent manner

2021 ◽  
Author(s):  
Christos M. Suriano ◽  
Jessica L. Verpeut ◽  
Neerav Kumar ◽  
Jie Ma ◽  
Caroline Jung ◽  
...  
Keyword(s):  
Nervous System ◽  
Gene Delivery ◽  
Dependent Manner ◽  
Neuronal Structure ◽  
Adeno Associated Virus ◽  
Gene Therapies ◽  
Efficient Gene ◽  
Core Feature ◽  
And Function ◽  
Dendritic Complexity

Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery in the nervous system. AAVs are widely used in research and are the basis of multiple FDA-approved gene therapies. Here, we find that the immune response to AAV's genome reduces dendritic complexity in mammalian cortex. Dendritic loss associated with AAV-mediated gene delivery occurs at experimentally-relevant titers, cannot be explained by responses to transgene expression or surgery, and is not restricted to a particular capsid serotype, encoded transgene, promoter, or production facility. AAV-associated dendritic loss is accompanied by a decrease in the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) and upregulation of immune molecules that can limit dendritic complexity and synaptic transmission. Blocking detection of unmethylated CpG-rich DNA via Toll-like receptor 9 (TLR9) protects dendritic complexity, suggesting that immunodetection of a core feature of the AAV genome triggers dendritic loss. These results reveal previously unsuspected impacts of AAV on neuronal structure and function and identify TLR9 inhibitors as important tools to improve the safety and efficacy of AAV-mediated gene delivery in the nervous system.

scholarly journals Tudor staphylococcal nuclease acts as a docking platform for stress granule components in Arabidopsis thaliana

2020 ◽  
Author(s):  
Emilio Gutierrez-Beltran ◽  
Pernilla H. Elander ◽  
Kerstin Dalman ◽  
Jose Luis Crespo ◽  
Panagiotis N. Moschou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Cell Biology ◽  
Gene Expression Regulation ◽  
De Novo ◽  
Staphylococcal Nuclease ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Stress Dependent ◽  
And Function

SUMMARYAdaptation to stress depends on the modulation of gene expression. Regulation of mRNA stability and degradation in stress granules (SGs), - cytoplasmic membraneless organelles composed of messenger ribonucleoprotein (mRNP) complexes, - plays an important role in fine-tuning of gene expression. In addition, SG formation can modulate stress signaling pathways by protein sequestration. Molecular composition, structure, and function of SGs in plants remain obscure. Recently, we established Tudor Staphylococcal Nuclease (TSN or Tudor-SN; also known as SND1) as integral component of SGs in Arabidopsis thaliana. Here, we combined purification of TSN interactome with cell biology, reverse genetics and bioinformatics to study composition and function of SGs in plants. We found that under both normal (in the absence of stress) and stress conditions TSN interactome is enriched in the homologues of known mammalian and yeast SG proteins, in addition to novel or plant-specific SG components. We estimate that upon stress perception, approximately half of TSN interactors are recruited to SGs de novo, in a stress-dependent manner, while another half represent a dense protein-protein interaction network pre-formed before onset of stress. Almost all TSN-interacting proteins are moderately or highly disordered and approximately 20% of them are predisposed for liquid-liquid phase separation (LLPS). This suggests that plant SGs, similarly to mammalian and yeast counterparts, are multicomponent viscous liquid droplets. Finally, we have discovered that evolutionary conserved SNF1-related protein kinase 1 (SnRK1) interacts with TSN in heat-induced SGs and that SnRK1 activation critically depends on the presence of TSN and formation of SGs. Altogether, our results establish TSN as a docking platform for SG-associated proteins and important stress signal mediator in plants.

scholarly journals PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

2015 ◽  
Vol 112 (6) ◽  
pp. 1874-1879 ◽  
Author(s):  
Ji Seung Ko ◽  
Gopal Pramanik ◽  
Ji Won Um ◽  
Ji Seon Shim ◽  
Dongmin Lee ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Transmembrane Protein ◽  
Protein Tyrosine Phosphatases ◽  
Excitatory Synaptic Transmission ◽  
Receptor Protein ◽  
Synapse Development ◽  
Dependent Manner ◽  
And Function ◽  
Receptor Protein Tyrosine Phosphatases

Leukocyte common antigen-related receptor protein tyrosine phosphatases—comprising LAR, PTPδ, and PTPσ—are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding–defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.

scholarly journals Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin

2011 ◽  
Vol 195 (7) ◽  
pp. 1171-1184 ◽  
Author(s):  
Nadine Schmidt ◽  
Mohammed Akaaboune ◽  
Nadesan Gajendran ◽  
Isabel Martinez-Pena y Valenzuela ◽  
Sarah Wakefield ◽  
...  
Keyword(s):  
Nervous System ◽  
Synaptic Transmission ◽  
Acetylcholine Receptors ◽  
Synapse Formation ◽  
Neuromuscular Synapse ◽  
Muscle Membrane ◽  
Erbb Signaling ◽  
Cultured Myotubes ◽  
The Stability ◽  
And Function

Neuregulin (NRG)/ErbB signaling is involved in numerous developmental processes in the nervous system, including synapse formation and function in the central nervous system. Although intensively investigated, its role at the neuromuscular synapse has remained elusive. Here, we demonstrate that loss of neuromuscular NRG/ErbB signaling destabilized anchoring of acetylcholine receptors (AChRs) in the postsynaptic muscle membrane and that this effect was caused by dephosphorylation of α-dystrobrevin1, a component of the postsynaptic scaffold. Specifically, in mice in which NRG signaling to muscle was genetically or pharmacologically abolished, postsynaptic AChRs moved rapidly from the synaptic to the perisynaptic membrane, and the subsynaptic scaffold that anchors the AChRs was impaired. These defects combined compromised synaptic transmission. We further show that blockade of NRG/ErbB signaling abolished tyrosine phosphorylation of α-dystrobrevin1, which reduced the stability of receptors in agrin-induced AChR clusters in cultured myotubes. Our data indicate that NRG/ErbB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of α-dystrobrevin1.

scholarly journals Methods for analyzing neuronal structure and activity in Caenorhabditis elegans

Genetics ◽  
2021 ◽  
Author(s):  
Scott W Emmons ◽  
Eviatar Yemini ◽  
Manuel Zimmer
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Fluorescent Probes ◽  
Synapse Formation ◽  
System Structure ◽  
Neuronal Structure ◽  
Fluorescent Reporters ◽  
C Elegans ◽  
Consistent Manner ◽  
And Function

Abstract The model research animal Caenorhabditis elegans has unique properties making it particularly advantageous for studies of the nervous system. The nervous system is composed of a stereotyped complement of neurons connected in a consistent manner. Here, we describe methods for studying nervous system structure and function. The transparency of the animal makes it possible to visualize and identify neurons in living animals with fluorescent probes. These methods have been recently enhanced for the efficient use of neuron-specific reporter genes. Because of its simple structure, for a number of years, C. elegans has been at the forefront of connectomic studies defining synaptic connectivity by electron microscopy. This field is burgeoning with new, more powerful techniques, and recommended up-to-date methods are here described that encourage the possibility of new work in C. elegans. Fluorescent probes for single synapses and synaptic connections have allowed verification of the EM reconstructions and for experimental approaches to synapse formation. Advances in microscopy and in fluorescent reporters sensitive to Ca2+ levels have opened the way to observing activity within single neurons across the entire nervous system.

scholarly journals A Role for Frizzled and Their Post-Translational Modifications in the Mammalian Central Nervous System

2021 ◽  
Vol 9 ◽  
Author(s):  
Patricia Pascual-Vargas ◽  
Patricia C. Salinas
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synapse Formation ◽  
Neuronal Circuits ◽  
Motor Tasks ◽  
Neuronal Connectivity ◽  
Post Translational Modifications ◽  
The Central Nervous System ◽  
And Function

The Wnt pathway is a key signalling cascade that regulates the formation and function of neuronal circuits. The main receptors for Wnts are Frizzled (Fzd) that mediate diverse functions such as neurogenesis, axon guidance, dendritogenesis, synapse formation, and synaptic plasticity. These processes are crucial for the assembly of functional neuronal circuits required for diverse functions ranging from sensory and motor tasks to cognitive performance. Indeed, aberrant Wnt–Fzd signalling has been associated with synaptic defects during development and in neurodegenerative conditions such as Alzheimer’s disease. New studies suggest that the localisation and stability of Fzd receptors play a crucial role in determining Wnt function. Post-translational modifications (PTMs) of Fzd are emerging as an important mechanism that regulates these Wnt receptors. However, only phosphorylation and glycosylation have been described to modulate Fzd function in the central nervous system (CNS). In this review, we discuss the function of Fzd in neuronal circuit connectivity and how PTMs contribute to their function. We also discuss other PTMs, not yet described in the CNS, and how they might modulate the function of Fzd in neuronal connectivity. PTMs could modulate Fzd function by affecting Fzd localisation and stability at the plasma membrane resulting in local effects of Wnt signalling, a feature particularly important in polarised cells such as neurons. Our review highlights the importance of further studies into the role of PTMs on Fzd receptors in the context of neuronal connectivity.

Sign in / Sign up

Export Citation Format

Share Document