scholarly journals The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior

2017 ◽  
Author(s):  
Nicholas P. Boyer ◽  
Caroline Monkiewicz ◽  
Sheryl S. Moy ◽  
Stephanie L. Gupton
Keyword(s):  
Brain Development ◽  
Axon Guidance ◽  
Neuronal Development ◽  
Sensorimotor Gating ◽  
Brain Regions ◽  
Class I ◽  
Guidance Cue ◽  
Evolutionarily Conserved ◽  
And Function ◽  
And Behavior

ABSTRACTSpecific class I members of the TRIM family of E3 ubiquitin ligases have been implicated in neuronal development from invertebrates to mammals. The single invertebrate class I TRIM and mammalian TRIM9 regulate axon branching and guidance in response to the axon guidance cue netrin-1, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Optiz Syndrome, characterized by midline defects and often mild intellectual disability. TRIM67 is the most evolutionarily conserved vertebrate class I TRIM, yet is the least studied. Here we show that TRIM67 interacts with both its closest paralog TRIM9 and the netrin receptor DCC, and is differentially enriched in specific brain regions at specific developmental points. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 display severe impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function and sensorimotor gating. Additionally, they exhibit abnormal anatomy of several brain regions, including the hippocampus, striatum and thalamus, as well as the corpus callosum. This study demonstrates the necessity for TRIM67 in appropriate brain development and function.SIGNIFICANCE STATEMENTAs a family, class I TRIM E3 ubiquitin ligases play important roles in neuronal development and function, potentially cooperatively. TRIM67 is the most evolutionarily conserved class I TRIM and is developmentally regulated and brain-enriched. Deletion of murine Trim67 results in malformations of a subset subcortical brain regions and of cortical and subcortical myelinated fiber tracts, as well as deficits in spatial memory, motor function, sociability and sensorimotor gating. We conclude that TRIM67 is critical for appropriate brain development and behavior, potentially downstream of the axon guidance cue netrin, and in cooperation with class I TRIM9.

Normalization Principles in Computational Neuroscience

2019 ◽  
Author(s):  
Kenway Louie ◽  
Paul W. Glimcher
Keyword(s):  
Information Processing ◽  
Computational Neuroscience ◽  
Linear Models ◽  
Brain Regions ◽  
Information Coding ◽  
Brain Organization ◽  
Contextual Modulation ◽  
Early Visual Cortex ◽  
And Function ◽  
And Behavior

A core question in systems and computational neuroscience is how the brain represents information. Identifying principles of information coding in neural circuits is critical to understanding brain organization and function in sensory, motor, and cognitive neuroscience. This provides a conceptual bridge between the underlying biophysical mechanisms and the ultimate behavioral goals of the organism. Central to this framework is the question of computation: what are the relevant representations of input and output, and what algorithms govern the input-output transformation? Remarkably, evidence suggests that certain canonical computations exist across different circuits, brain regions, and species. Such computations are implemented by different biophysical and network mechanisms, indicating that the unifying target of conservation is the algorithmic form of information processing rather than the specific biological implementation. A prime candidate to serve as a canonical computation is divisive normalization, which scales the activity of a given neuron by the activity of a larger neuronal pool. This nonlinear transformation introduces an intrinsic contextual modulation into information coding, such that the selective response of a neuron to features of the input is scaled by other input characteristics. This contextual modulation allows the normalization model to capture a wide array of neural and behavioral phenomena not captured by simpler linear models of information processing. The generality and flexibility of the normalization model arises from the normalization pool, which allows different inputs to directly drive and suppress a given neuron, effectively separating information that drives excitation and contextual modulation. Originally proposed to describe responses in early visual cortex, normalization has been widely documented in different brain regions, hierarchical levels, and modalities of sensory processing; furthermore, recent work shows that the normalization extends to cognitive processes such as attention, multisensory integration, and decision making. This ubiquity reinforces the canonical nature of the normalization computation and highlights the importance of an algorithmic framework in linking biological mechanism and behavior.

scholarly journals cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development

2018 ◽  
Vol 115 (40) ◽  
pp. E9449-E9458 ◽  
Author(s):  
Feng Zhang ◽  
Yaqing Wang ◽  
Tao Wang ◽  
Li Yao ◽  
Sin Man Lam ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Development ◽  
Neuronal Development ◽  
Critical Role ◽  
Conditional Knockout ◽  
Copii Vesicle ◽  
Membrane Components ◽  
And Function ◽  
Cellular Components ◽  
Abnormal Behaviors

Normal neural development is essential for the formation of neuronal networks and brain function. Cutaneous T cell lymphoma-associated antigen 5 (cTAGE5)/meningioma expressed antigen 6 (MEA6) plays a critical role in the secretion of proteins. However, its roles in the transport of nonsecretory cellular components and in brain development remain unknown. Here, we show that cTAGE5/MEA6 is important for brain development and function. Conditional knockout ofcTAGE5/MEA6in the brain leads to severe defects in neural development, including deficits in dendrite outgrowth and branching, spine formation and maintenance, astrocyte activation, and abnormal behaviors. We reveal that loss of cTAGE5/MEA6 affects the interaction between the coat protein complex II (COPII) components, SAR1 and SEC23, leading to persistent activation of SAR1 and defects in COPII vesicle formation and transport from the endoplasmic reticulum to the Golgi, as well as disturbed trafficking of membrane components in neurons. These defects affect not only the transport of materials required for the development of dendrites and spines but also the signaling pathways required for neuronal development. Because mutations in cTAGE5/MEA6 have been found in patients with Fahr’s disease, our study potentially also provides insight into the pathogenesis of this disorder.

scholarly journals miR-375 Inhibits Differentiation of Neurites by Lowering HuD Levels

2010 ◽  
Vol 30 (17) ◽  
pp. 4197-4210 ◽  
Author(s):  
Kotb Abdelmohsen ◽  
Emmette R. Hutchison ◽  
Eun Kyung Lee ◽  
Yuki Kuwano ◽  
Mihee M. Kim ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Untranslated Region ◽  
Neuronal Development ◽  
Rna Binding ◽  
Developmentally Regulated ◽  
Cytoskeleton Organization ◽  
Evolutionarily Conserved ◽  
Mouse Hippocampus ◽  
Regulated Gene Expression ◽  
And Function

ABSTRACT Neuronal development and plasticity are maintained by tightly regulated gene expression programs. Here, we report that the developmentally regulated microRNA miR-375 affects dendrite formation and maintenance. miR-375 overexpression in mouse hippocampus potently reduced dendrite density. We identified the predominantly neuronal RNA-binding protein HuD as a key effector of miR-375 influence on dendrite maintenance. Heterologous reporter analysis verified that miR-375 repressed HuD expression through a specific, evolutionarily conserved site on the HuD 3′ untranslated region. miR-375 overexpression lowered both HuD mRNA stability and translation and recapitulated the effects of HuD silencing, which reduced the levels of target proteins with key functions in neuronal signaling and cytoskeleton organization (N-cadherin, PSD-95, RhoA, NCAM1, and integrin α1). Moreover, the increase in neurite outgrowth after brain-derived neurotrophic factor (BDNF) treatment was diminished by miR-375 overexpression; this effect was rescued by reexpression of miR-375-refractory HuD. Our findings indicate that miR-375 modulates neuronal HuD expression and function, in turn affecting dendrite abundance.

scholarly journals Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 191
Author(s):  
Rosa Manzoli ◽  
Lorenzo Badenetti ◽  
Michela Rubin ◽  
Enrico Moro
Keyword(s):  
Axon Guidance ◽  
Neural Circuit ◽  
Axonal Guidance ◽  
Lysosomal Storage ◽  
Relevant Research ◽  
Lysosomal Function ◽  
Guidance Cue ◽  
Tight Connection ◽  
And Function ◽  
Storage Disorders

Axonal trajectories and neural circuit activities strongly rely on a complex system of molecular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely understood intracellular mechanisms, that in part rely on endocytic and autophagic cascades. Based on their pivotal role in both pathways, lysosomes are emerging as a key hub in the sophisticated regulation of axonal guidance cue delivery, localization, and function. In this review, we will attempt to collect some of the most relevant research on the tight connection between lysosomal function and axon guidance regulation, providing some proof of concepts that may be helpful to understanding the relation between lysosomal storage disorders and neurodegenerative diseases.

scholarly journals Genome-enabled discovery of evolutionary divergence in brains and behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chinar Patil ◽  
Jonathan B. Sylvester ◽  
Kawther Abdilleh ◽  
Michael W. Norsworthy ◽  
Karen Pottin ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Natural Populations ◽  
Bmp Signaling ◽  
Evolutionary Divergence ◽  
Genetic Changes ◽  
Form And Function ◽  
Brain Gene Expression ◽  
Evolutionarily Conserved ◽  
And Function ◽  
And Behavior

AbstractLake Malawi cichlid fishes exhibit extensive divergence in form and function built from a relatively small number of genetic changes. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. Genome regions near differentiated variants are enriched for craniofacial, neural and behavioral categories. Following leads from genome sequence, we used rock- vs. sand-species and their hybrids to (i) delineate the push–pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results demonstrate how divergent genome sequences can predict differences in key evolutionary traits. We highlight the promise of evolutionary reverse genetics—the inference of phenotypic divergence from unbiased genome sequencing and then empirical validation in natural populations.

scholarly journals Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

2020 ◽  
Vol 21 (16) ◽  
pp. 5850 ◽  
Author(s):  
Sabrina I. Hanswijk ◽  
Marcia Spoelder ◽  
Ling Shan ◽  
Michel M. M. Verheij ◽  
Otto G. Muilwijk ◽  
...  
Keyword(s):  
Brain Development ◽  
Animal Studies ◽  
Fetal Brain ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Hyperactivity Disorder ◽  
Maternal Genotype ◽  
Brain Structure And Function ◽  
And Function ◽  
And Behavior

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other’s impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

scholarly journals Genome-enabled discovery of evolutionary divergence in brains and behavior 

2021 ◽  
Author(s):  
Chinar Patil ◽  
Jonathan Sylvester ◽  
Kawther Abdilleh ◽  
Michael W. Norsworthy ◽  
Karen Pottin ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Natural Populations ◽  
Bmp Signaling ◽  
Evolutionary Divergence ◽  
Genetic Changes ◽  
Form And Function ◽  
Brain Gene Expression ◽  
Evolutionarily Conserved ◽  
And Function ◽  
And Behavior

Abstract Lake Malawi cichlid fishes exhibit extensive divergence in form and function built from a relatively small number of genetic changes. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. Genome regions near differentiated variants are enriched for craniofacial, neural and behavioral categories. Following leads from genome sequence, we used rock- vs. sand- species and their hybrids to (i) delineate the push-pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results demonstrate how divergent genome sequences can predict differences in key evolutionary traits. We highlight the promise of evolutionary reverse genetics – the inference of divergence in phenotype from genome sequencing in natural populations.

scholarly journals The ubiquitylome of developing cortical neurons

2020 ◽  
Author(s):  
Shalini Menon ◽  
Dennis Goldfarb ◽  
Emily M. Cousins ◽  
M. Ben Major ◽  
Stephanie L. Gupton
Keyword(s):  
Axon Guidance ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Cortical Neurons ◽  
Spatial Learning And Memory ◽  
Form And Function ◽  
Guidance Cue ◽  
Morphological Responses ◽  
And Function

AbstractTRIM9 and TRIM67 are neuronally-enriched E3 ubiquitin. Both genes are required for neuronal morphological responses to the axon guidance cue netrin-1. For example, our previously published work demonstrated that the actin polymerase VASP and the netrin receptor DCC exhibit TRIM9 dependent ubiquitylation that is lost upon netrin stimulation. Deletion of either gene in the mouse results in subtle neuroanatomical anomalies yet overt deficits in spatial learning and memory. Despite their role in neuronal form and function, the identity of few TRIM9 or TRIM67 substrates are known. Here we performed ubiquitin remnant profiling approach in cultured wildtype and knockout murine embryonic cortical neurons to identify ubiquitylated peptides and proteins, with the ultimate goal of identifying substrates of TRIM9 and TRIM67 that exhibited reduced ubiquitylation in the absence of the ligase. This work reveals the ubiquitylome of developing cortical neurons.

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