scholarly journals LNX1/LNX2 proteins: functions in neuronal signalling and beyond

2018 ◽  
Vol 2 (2) ◽  
Author(s):  
Paul W. Young
Keyword(s):  
Nervous System ◽  
Cell Fate ◽  
Synapse Formation ◽  
Osteoclast Differentiation ◽  
Embryonic Patterning ◽  
Double Knockout ◽  
Protein Levels ◽  
Neuronal Signalling ◽  
Cell Fate Determinant

Ligand of NUMB Protein X1 and X2 (LNX1 and LNX2) are E3 ubiquitin ligases, named for their ability to interact with and promote the degradation of the cell fate determinant protein NUMB. On this basis they are thought to play a role in modulating NUMB/NOTCH signalling during processes such as cortical neurogenesis. However, LNX1/2 proteins can bind, via their four PDZ (PSD95, DLGA, ZO-1) domains, to an extraordinarily large number of other proteins besides NUMB. Many of these interactions suggest additional roles for LNX1/2 proteins in the nervous system in areas such as synapse formation, neurotransmission and regulating neuroglial function. Twenty years on from their initial discovery, I discuss here the putative neuronal functions of LNX1/2 proteins in light of the anxiety-related phenotype of double knockout mice lacking LNX1 and LNX2 in the central nervous system (CNS). I also review what is known about non-neuronal roles of LNX1/2 proteins, including their roles in embryonic patterning and pancreas development in zebrafish and their possible involvement in colorectal cancer (CRC), osteoclast differentiation and immune function in mammals. The emerging picture places LNX1/2 proteins as potential regulators of multiple cellular signalling processes, but in many cases the physiological significance of such roles remains only partly validated and needs to be considered in the context of the tight control of LNX1/2 protein levels in vivo.

scholarly journals Transcriptomic analysis reveals a role for the nervous system in regulating growth and development of Fasciola hepatica juveniles

2022 ◽  
Author(s):  
Emily Robb ◽  
Erin McCammick ◽  
Duncan Wells ◽  
Paul McVeigh ◽  
Erica Gardiner ◽  
...  
Keyword(s):  
Nervous System ◽  
Rapid Growth ◽  
Growth And Development ◽  
Liver Fluke ◽  
Fasciola Hepatica ◽  
Expression Profiles ◽  
Neuronal Signalling ◽  
Growth Development

Fasciola spp. liver fluke have significant impacts in veterinary and human medicine. The absence of a vaccine and increasing anthelmintic resistance threaten sustainable control and underscore the need for novel flukicides. Functional genomic approaches underpinned by in vitro culture of juvenile Fasciola hepatica facilitate control target validation in the most pathogenic life stage. Comparative transcriptomics of in vitro and in vivo maintained 21 day old F. hepatica finds that 86% of genes are expressed at similar levels across maintenance treatments suggesting commonality in core biological functioning within these juveniles. Phenotypic comparisons revealed higher cell proliferation and growth rates in the in vivo juveniles compared to their in vitro counterparts. These phenotypic differences were consistent with the upregulation of neoblast-like stem cell and cell-cycle associated genes in in vivo maintained worms. The more rapid growth/development of in vivo juveniles was further evidenced by a switch in cathepsin protease expression profiles, dominated by cathepsin B in in vitro juveniles and then by cathepsin L in in vivo juveniles. Coincident with more rapid growth/development was the marked downregulation of both classical and peptidergic neuronal signalling components in in vivo maintained juveniles, supporting a role for the nervous system in regulating liver fluke growth and development. Differences in the miRNA complements of in vivo and in vitro juveniles identified 31 differentially expressed miRNAs, notably fhe-let-7a-5p , fhe-mir-124-3p and, miRNAs predicted to target Wnt-signalling, supporting a key role for miRNAs in driving the growth/developmental differences in the in vitro and in vivo maintained juvenile liver fluke. Widespread differences in the expression of neuronal genes in juvenile fluke grown in vitro and in vivo expose significant interplay between neuronal signalling and the rate of growth/development, encouraging consideration of neuronal targets in efforts to dysregulate growth/development for parasite control.

scholarly journals 09 Could DLX2 regulation of neural progenitor cell fate contribute to differentiation of diffuse intrinsic pontine glioma (DIPG)?

2018 ◽  
Vol 45 (S3) ◽  
pp. S16-S16
Author(s):  
M Nevin ◽  
X Song ◽  
S Japoni ◽  
J Zagozewski ◽  
Q Jiang ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neural Progenitor Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Gabaergic Interneuron ◽  
Acid Decarboxylase ◽  
Pontine Glioma ◽  
Double Knockout ◽  
Promoter Sequences

Introduction: Diffuse intrinsic pontine glioma (DIPG) is refractory to therapy. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided new insights. The DLX homeobox genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse loses tangential GABAergic interneuron migration to the neocortex. We have identified genes that encode glutamic acid decarboxylase (GAD) enzymes as direct targets of DLX1/DLX2. In DIPG patients with H3.3 K27M mutations there is decreased Dlx2 and increased expression of the myelin transcription factor, Myt1. Methods and Results: We used bioinformatics approaches and chromatin immunoprecipitation (ChIP) assays to identify Olig2, Nkx2.2 and Myt1 promoter sequences as candidate DLX2 targets in vivo. DNA binding specificity was confirmed. The functional consequences of Dlx2 co-expression with reporter constructs of ChIP-isolated promoter fragments of Olig2 and Nkx2.2 demonstrated repression of gene targets in vitro. qPCR showed increased Olig2 and Nkx2.2 expression in the DKO forebrain. Stable transfection of a murine DIPG cell line with Dlx2 resulted in increased Gad1 and Gad2 and decreased Olig2 and Nkx2.2 expression. Of significance, we demonstrated decreased expression of H3.3 K27M and restoration of H3.3 K27 tri-methylation (me3). Conclusions: DLX transcription factors promote GABAergic interneuron and concomitant inhibition of oligodendroglial differentiation in neural progenitors by repression of a suite of genes including Olig2 and Nkx2.2. Restoration of H3 K27me3 expression in DIPG provides a promising lead towards exploration of differentiation as a therapeutic strategy for DIPG.

scholarly journals Control of skeletal morphogenesis by the Hippo-YAP/TAZ pathway

Development ◽  
2020 ◽  
Vol 147 (21) ◽  
pp. dev187187
Author(s):  
Hannah K. Vanyai ◽  
Fabrice Prin ◽  
Oriane Guillermin ◽  
Bishara Marzook ◽  
Stefan Boeing ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Control Cell ◽  
Tissue Growth ◽  
Double Knockout ◽  
Cartilage Growth ◽  
Chondrocyte Proliferation ◽  
Specific Expression

ABSTRACTThe Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.

scholarly journals From Synapses to Circuits, Astrocytes Regulate Behavior

2022 ◽  
Vol 15 ◽  
Author(s):  
Krissy A. Lyon ◽  
Nicola J. Allen
Keyword(s):  
Nervous System ◽  
Synapse Formation ◽  
Behavioral Flexibility ◽  
Active Role ◽  
Neuronal Synapses ◽  
Astrocyte Heterogeneity ◽  
Formation Function ◽  
Nervous System Function ◽  
And Behavior

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

scholarly journals PDK1 is a negative regulator of axon regeneration

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Hyemin Kim ◽  
Jinyoung Lee ◽  
Yongcheol Cho
Keyword(s):  
Nervous System ◽  
Axon Regeneration ◽  
Dorsal Root Ganglion Neurons ◽  
Negative Regulator ◽  
Protein Levels ◽  
Adult Mice ◽  
The Central Nervous System ◽  
Ganglion Neurons

AbstractAxon regeneration in the central nervous system is inefficient. However, the neurons in the peripheral nervous system display robust regeneration after injury, indicating that axonal regeneration is differentially controlled under various conditions. To identify those molecules regulating axon regeneration, comparative analysis from dorsal root ganglion neurons at embryonic or adult stages is utilized, which reveals that PDK1 is functions as a negative regulator of axon regeneration. PDK1 is downregulated in embryonic neurons after axotomy. In contrast, sciatic nerve axotomy upregulated PDK1 at protein levels from adult mice. The knockdown of PDK1 or the chemical inhibition of PDK1 promotes axon regeneration in vitro and in vivo. Here we present PDK1 as a new player to negatively regulate axon regeneration and as a potential target in the development of therapeutic applications.

scholarly journals Mitochondrial p53 Contributes to Reovirus-Induced Neuronal Apoptosis and Central Nervous System Injury in a Mouse Model of Viral Encephalitis

2016 ◽  
Vol 90 (17) ◽  
pp. 7684-7691 ◽  
Author(s):  
Yonghua Zhuang ◽  
Heather M. Berens-Norman ◽  
J. Smith Leser ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Fate ◽  
Tissue Injury ◽  
Ex Vivo ◽  
P53 Protein ◽  
Cns Injury ◽  
Expression Levels ◽  
Reovirus Infection ◽  
Protein Levels

ABSTRACTThe tumor suppressor p53 plays a critical part in determining cell fate both as a regulator of the transcription of several proapoptotic genes and through its binding interactions with Bcl-2 family proteins at mitochondria. We now demonstrate that p53 protein levels are increased in infected brains during reovirus encephalitis. This increase occurs in the cytoplasm of reovirus-infected neurons and is associated with the activation of caspase 3. Increased levels of p53 in reovirus-infected brains are not associated with increased expression levels of p53 mRNA, suggesting that p53 regulation occurs at the protein level. Increased levels of p53 are also not associated with the increased expression levels of p53-regulated, proapoptotic genes. In contrast, upregulated p53 accumulates in mitochondria. Previous reports demonstrated that the binding of p53 to Bak at mitochondria causes Bak activation and results in apoptosis. We now show that Bak is activated and that activated Bak is bound to p53 during reovirus encephalitis. In addition, survival is enhanced in reovirus-infected Bak−/−mice compared to controls, demonstrating a role for Bak in reovirus pathogenesis. Inhibition of the mitochondrial translocation of p53 with pifithrin μ prevents the formation of p53/Bak complexes following reovirus infection ofex vivobrain slice cultures and results in decreased apoptosis and tissue injury. These results suggest that the mitochondrial localization of p53 regulates reovirus-induced pathogenesis in the central nervous system (CNS) through its interactions with Bak.IMPORTANCEThere are virtually no specific treatments of proven efficacy for virus-induced neuroinvasive diseases. A better understanding of the pathogenesis of virus-induced CNS injury is crucial for the rational development of novel therapies. Our studies demonstrate that p53 is activated in the brain following reovirus infection and may provide a therapeutic target for virus-induced CNS disease.

scholarly journals Cyclin E Acts under the Control of Hox-Genes as a Cell Fate Determinant in the Developing Central Nervous System

Cell Cycle ◽  
2005 ◽  
Vol 4 (3) ◽  
pp. 422-425 ◽  
Author(s):  
Christian Berger ◽  
S.K. Pallavi ◽  
Mohit Prasad ◽  
L.S. Shashidhara ◽  
Gerhard M. Technau
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Fate ◽  
Hox Genes ◽  
Cyclin E ◽  
Cell Fate Determinant ◽  
A Cell

scholarly journals cnd-1/NeuroD1 Functions with the Homeobox Gene ceh-5/Vax2 and Hox Gene ceh-13/labial To Specify Aspects of RME and DD Neuron Fate in Caenorhabditis elegans

2020 ◽  
Vol 10 (9) ◽  
pp. 3071-3085
Author(s):  
Wendy Aquino-Nunez ◽  
Zachery E Mielko ◽  
Trae Dunn ◽  
Elise M Santorella ◽  
Ciara Hosea ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Neural Development ◽  
Nervous System Development ◽  
Cell Fate Specification ◽  
Hox Gene ◽  
Fate Specification

Abstract Identifying the mechanisms behind neuronal fate specification are key to understanding normal neural development in addition to neurodevelopmental disorders such as autism and schizophrenia. In vivo cell fate specification is difficult to study in vertebrates. However, the nematode Caenorhabditis elegans, with its invariant cell lineage and simple nervous system of 302 neurons, is an ideal organism to explore the earliest stages of neural development. We used a comparative transcriptome approach to examine the role of cnd-1/NeuroD1 in C. elegans nervous system development and function. This basic helix-loop-helix transcription factor is deeply conserved across phyla and plays a crucial role in cell fate specification in both the vertebrate nervous system and pancreas. We find that cnd-1 controls expression of ceh-5, a Vax2-like homeobox class transcription factor, in the RME head motorneurons and PVQ tail interneurons. We also show that cnd-1 functions redundantly with the Hox gene ceh-13/labial in defining the fate of DD1 and DD2 embryonic ventral nerve cord motorneurons. These data highlight the utility of comparative transcriptomes for identifying transcription factor targets and understanding gene regulatory networks.

scholarly journals Asymmetry and Cell Fate in Stem Cells and Cancer

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-45-SCI-45
Author(s):  
Tannishtha Reya
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Imaging System ◽  
Conflicts Of Interest ◽  
Asymmetric Division ◽  
Hematologic Malignancies ◽  
Cell Fate Determinant ◽  
In Vivo Imaging System

Abstract Our research focuses on the signals that control stem cell self-renewal and how these signals are hijacked in cancer. Using genetic models, we have shown that classic developmental signaling pathways such as Wnt and Hedgehog play key roles in stem cell growth and regeneration and are dysregulated during leukemia development. In addition, we have used real-time imaging strategies to show that stem cells have the capacity to undergo both symmetric and asymmetric division, and that shifts in the balance between these modes of division are controlled by the microenvironment and subverted by oncogenes. This work led to the discovery that regulators of asymmetric division, such as the cell fate determinant Musashi, can promote aggressive leukemias and may serve as critical targets for diagnostics and therapy in hematologic malignancies. Most recently, we have developed a high resolution in vivo imaging system that has allowed us to begin to map the behavior and interactions of stem cells with the microenvironment within living animals and to define how these change during cancer formation. Disclosures No relevant conflicts of interest to declare.

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