scholarly journals TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus

Development ◽  
2020 ◽  
Vol 147 (16) ◽  
pp. dev190181
Author(s):  
Marcin Andrzej Lipiec ◽  
Joanna Bem ◽  
Kamil Koziński ◽  
Chaitali Chakraborty ◽  
Joanna Urban-Ciećko ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Migration ◽  
Embryonic Development ◽  
Axon Guidance ◽  
Specific Cell ◽  
Thalamic Neurons ◽  
Master Regulators ◽  
Vertebrate Brain ◽  
Control Stage

ABSTRACTNeuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2−/− embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.

scholarly journals TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

2019 ◽  
Author(s):  
Marcin Andrzej Lipiec ◽  
Kamil Koziński ◽  
Tomasz Zajkowski ◽  
Joanna Bem ◽  
Joanna Urban-Ciećko ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Developmental Stages ◽  
Network Control ◽  
Conditional Knockout ◽  
Specific Cell ◽  
Thalamic Neurons ◽  
Vertebrate Brain ◽  
Control Stage ◽  
Cell Clustering

AbstractNeuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but few examples of such regulators have been provided in vertebrates. TCF7L2 has been identified as a regulator of efferent outgrowth in the thalamus and habenula. We used a complete and conditional knockout of Tcf7l2 in mice to investigate the hypothesis that TCF7L2 plays a dual role in thalamic neuron differentiation and functions as a terminal selector. Connectivity and cell clustering was disrupted in the thalamo-habenular region in Tcf7l2-/- embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with postnatal Tcf7l2 knockout, the induction of genes that confer terminal electrophysiological features of thalamic neurons was impaired. Many of these genes proved to be TCF7L2 direct targets. The role of TCF7L2 in thalamic terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that maintain regional transcriptional network, control stage-specific genetic programs and induce terminal selection.StatementThe study describes a role of TCF7L2 in neuronal differentiation of thalamic glutamatergic neurons at two developmental stages, highlighting its involvement in the postnatal establishment of critical thalamic electrophysiological features.

Eph receptors and ephrins: effectors of morphogenesis

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2033-2044 ◽  
Author(s):  
N. Holder ◽  
R. Klein
Keyword(s):  
Cell Migration ◽  
Pattern Formation ◽  
Axon Guidance ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Structural Domains ◽  
Eph Receptor

Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.

scholarly journals The role of the retinoids in schizophrenia: genomic and clinical perspectives

2019 ◽  
Vol 25 (4) ◽  
pp. 706-718 ◽  
Author(s):  
William R. Reay ◽  
Murray J. Cairns
Keyword(s):  
Vitamin A ◽  
Embryonic Development ◽  
Human Brain ◽  
Observational Data ◽  
Large Scale ◽  
Dietary Intervention ◽  
Biological Processes ◽  
Master Regulators ◽  
Genome Wide

Abstract Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, however, is required to expand on the largely observational data collected thus far and confirm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia.

scholarly journals Role of a New Rho Family Member in Cell Migration and Axon Guidance in C. elegans

Cell ◽  
1997 ◽  
Vol 90 (5) ◽  
pp. 883-894 ◽  
Author(s):  
Ilan D Zipkin ◽  
Rachel M Kindt ◽  
Cynthia J Kenyon
Keyword(s):  
Cell Migration ◽  
Axon Guidance ◽  
Family Member ◽  
C Elegans ◽  
Rho Family

scholarly journals Cell migration and axon guidance at the border between central and peripheral nervous system

Science ◽  
2019 ◽  
Vol 365 (6456) ◽  
pp. eaaw8231 ◽  
Author(s):  
Tracey A. C. S. Suter ◽  
Alexander Jaworski
Keyword(s):  
Nervous System ◽  
Cell Migration ◽  
Embryonic Development ◽  
Axon Guidance ◽  
Peripheral Nervous System ◽  
Glial Cell ◽  
Molecular Mechanisms ◽  
Control Cell ◽  
Cell Types ◽  
Open Questions

The central and peripheral nervous system (CNS and PNS, respectively) are composed of distinct neuronal and glial cell types with specialized functional properties. However, a small number of select cells traverse the CNS-PNS boundary and connect these two major subdivisions of the nervous system. This pattern of segregation and selective connectivity is established during embryonic development, when neurons and glia migrate to their destinations and axons project to their targets. Here, we provide an overview of the cellular and molecular mechanisms that control cell migration and axon guidance at the vertebrate CNS-PNS border. We highlight recent advances on how cell bodies and axons are instructed to either cross or respect this boundary, and present open questions concerning the development and plasticity of the CNS-PNS interface.

scholarly journals Netrin instructs synaptic vesicle clustering through Rac GTPase, MIG-10, and the actin cytoskeleton

2012 ◽  
Vol 197 (1) ◽  
pp. 75-88 ◽  
Author(s):  
Andrea K.H. Stavoe ◽  
Daniel A. Colón-Ramos
Keyword(s):  
Cell Migration ◽  
Subcellular Localization ◽  
Actin Cytoskeleton ◽  
Axon Guidance ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Rac Gtpase ◽  
Signaling Modules

Netrin is a chemotrophic factor known to regulate a number of neurodevelopmental processes, including cell migration, axon guidance, and synaptogenesis. Although the role of Netrin in synaptogenesis is conserved throughout evolution, the mechanisms by which it instructs synapse assembly are not understood. Here we identify a mechanism by which the Netrin receptor UNC-40/DCC instructs synaptic vesicle clustering in vivo. UNC-40 localized to presynaptic regions in response to Netrin. We show that UNC-40 interacted with CED-5/DOCK180 and instructed CED-5 presynaptic localization. CED-5 in turn signaled through CED-10/Rac1 and MIG-10/Lamellipodin to organize the actin cytoskeleton in presynaptic regions. Localization of this signaling pathway to presynaptic regions was necessary for synaptic vesicle clustering during synapse assembly but not for the subcellular localization of active zone proteins. Thus, vesicle clustering and localization of active zone proteins are instructed by separate pathways downstream of Netrin. Our data indicate that signaling modules known to organize the actin cytoskeleton during guidance can be co-opted to instruct synaptic vesicle clustering.

scholarly journals The Physiology of Homeoprotein Transduction

2018 ◽  
Vol 98 (4) ◽  
pp. 1943-1982 ◽  
Author(s):  
Ariel A. Di Nardo ◽  
Julia Fuchs ◽  
Rajiv L. Joshi ◽  
Kenneth L. Moya ◽  
Alain Prochiantz
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Transcription Factors ◽  
Cell Migration ◽  
Axon Guidance ◽  
Dna Binding Domain ◽  
Autonomous Regulation ◽  
Physiological Homeostasis ◽  
The Central Nervous System

The homeoprotein family comprises ~300 transcription factors and was long seen as primarily involved in developmental programs through cell autonomous regulation. However, recent evidence reveals that many of these factors are also expressed in the adult where they exert physiological functions not yet fully deciphered. Furthermore, the DNA-binding domain of most homeoproteins contains two signal sequences allowing their secretion and internalization, thus intercellular transfer. This review focuses on this new-found signaling in cell migration, axon guidance, and cerebral cortex physiological homeostasis and speculates on how it may play important roles in early arealization of the neuroepithelium. It also describes the use of homeoproteins as therapeutic proteins in mouse models of diseases affecting the central nervous system, in particular Parkinson disease and glaucoma.

scholarly journals A repressor-decay timer for robust temporal patterning in embryonic Drosophila neuroblast lineages

2018 ◽  
Author(s):  
Inna Averbukh ◽  
Sen-Lin Lai ◽  
Chris Q. Doe ◽  
Naama Barkai
Keyword(s):  
Transcription Factors ◽  
Embryonic Development ◽  
Neural Progenitors ◽  
Evolutionary Design ◽  
Temporal Patterning ◽  
Regulatory Circuit ◽  
Parameter Variations ◽  
Theory And Experiments

AbstractBiological timers synchronize patterning processes during embryonic development. In the Drosophila embryo, neural progenitors (neuroblasts; NBs) produce a sequence of unique neurons whose identities depend on the sequential expression of temporal transcription factors (TTFs). The stereotypy and precision of the NB lineages indicate reproducible temporal progression of the TTF timer. To examine the basis of this robustness, we combine theory and experiments. The TTF timer is commonly described as a relay of activators, but its regulatory circuit is also consistent with a repressor-decay timer, in which expression of each TTF begins once its repressor is sufficiently reduced. We find that repressor-decay timers are more robust to parameter variations compared to activator-relay timers. This suggests that the in-vivo TTF sequence progresses primarily by repressor-decay, a prediction that we support experimentally. Our results emphasize the role of robustness in the evolutionary design of patterning circuits.

scholarly journals Multiple roles of syndecan-4 during myoblast migration

2021 ◽  
Author(s):  
Dániel Becsky
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Cell Migration ◽  
Embryonic Development ◽  
Cell Polarity ◽  
Focal Adhesion ◽  
Muscle Disease ◽  
Satellite Stem Cells ◽  
Migrating Cells

Background and purpose: Cell migration is one of the cornerstones of regeneration processes, as it is necessary for wound healing, and also required for embryonic development, immune system activation, or tumor metastasis formation. Skeletal muscle has a special, advanced dynamism that allows it to adapt to various impacts and recover successfully after an injury, exercise, or muscle disease. Satellite stem cells are activated by local damage during muscle regeneration, and after asymmetric division, myoblasts (i.e., activated satellite cells) migrate to the site of injury, differentiate, and fuse to form muscle fibers. Migration of the cells requires cellular polarization, the creation of leading and trailing edges, as well as the proper orientation and positioning of organelles inside the cell. Efficient migration also requires the presence of an asymmetrical front-to-rear calcium (Ca2+) gradient to regulate focal adhesion assembly and actomyosin contractility. The transmembrane proteoglycan syndecan-4 (SDC4), which is one of the cell surface markers of resting and activated satellite stem cells, is involved in the formation of focal adhesions. Furthermore, SDC4 plays a variety of roles in signal transduction processes, including controlling the function of the small GTPase Rac1 by binding to and inhibiting the activity of T-lymphoma invasion and metastasis-1 (Tiam1), a guanine nucleotide exchange factor for Rac1 (Ras-related C3 botulinum toxin substrate 1) GTPase. Cell migration also requires Rac1-mediated actin remodeling. SDC4 knockout mice are unable to regenerate damaged muscle; however, its underlying precise mechanism is unclear; therefore, our aim was to analyze the role of SDC4 in myoblast migration. Experimental approaches: To achieve SDC4 knockdown, C2C12 murine myoblast cells were transfected stably with plasmids expressing short hairpin RNAs (shRNAs) specific for mouse SDC4 (shSDC4#1 and shSDC4#2) or a scrambled target sequence. To study cell migration, time-lapse images were captured at 37 °C and 5% CO2 using a high-content imaging system for single-cell tracking or wound scratch assay was performed. To evaluate the movement of the single cells, the cell nuclei were tracked with ImageJ and CellTracker software. Super-resolution direct stochastic optical reconstruction microscopy (dSTORM) measurements were performed for the nanoscale analysis of the lamellipodial actin network of the migrating cells. To study the intracellular Ca2+ level, Fluo-4 and Fura Red indicators were applied. Immunofluorescence cytochemistry was performed to analyze the distribution of SDC4, Tiam1, centrosomes, FAK (focal adhesion kinase) or GM130 (anti- Golgi matrix protein of 130 kDa) followed by wide-field fluorescence or confocal microscopy. Image analysis was performed with ImageJ. Rac1 was inhibited by NSC23766 treatment during the measurements (50 µM). Key results: Silencing of SDC4 disrupts the correct polarization of migrating mammalian myoblasts. SDC4 knockdown completely abolished the intracellular Ca2+ gradient, abrogated centrosome reorientation, and thus decreased cell motility, demonstrating the role of SDC4 in cell polarity. Additionally, SDC4 exhibited a polarized distribution during migration. SDC4 knockdown cells exhibited decreases in the total movement distance during migration, maximum and vectorial distances from the starting point, as well as average and maximum cell speeds. Analysis of the dSTORM images of SDC4 knockdown cells revealed nanoscale changes in the actin cytoskeletal architecture, such as decreases in the numbers of branches and individual branch lengths in the lamellipodia of the migrating cells. The Rac1 inhibitor NSC23766 did not restore the migration capacity of SDC4 silenced cells; in fact, it reduced it further. SDC4 knockdown decreased the directional persistence of migration, abrogated the polarized, asymmetric distribution of Tiam1, and reduced the total Tiam1 level of the cells. Conclusion: According to our results, SDC4 affects the migration of C2C12 myoblasts and modulates cell polarity by influencing centrosome positioning, intracellular Ca2+ and Tiam1 distribution. These findings may promote greater understanding the essential role of SDC4 in the embryonic development and postnatal regeneration of skeletal muscle. Given the ubiquitous expression and crucial role of SDC4 in cell migration, we conclude that our findings can facilitate understanding the general role of SDC4 during cell migration.

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