scholarly journals Adult Upper Cortical Layer Specific Transcription Factor CUX2 Is Expressed in Transient Subplate and Marginal Zone Neurons of the Developing Human Brain

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 415
Author(s):  
Terezija Miškić ◽  
Ivica Kostović ◽  
Mladen-Roko Rašin ◽  
Željka Krsnik
Keyword(s):  
Transcription Factor ◽  
Human Brain ◽  
Cortical Neurons ◽  
Marginal Zone ◽  
Synapse Formation ◽  
Cortical Layer ◽  
Cortical Plate ◽  
Projection Neurons ◽  
Cortical Layers ◽  
Spine Development

Cut-Like Homeobox 2 (Cux2) is a transcription factor involved in dendrite and spine development, and synapse formation of projection neurons placed in mouse upper neocortical layers. Therefore, Cux2 is often used as an upper layer marker in the mouse brain. However, expression of its orthologue CUX2 remains unexplored in the human fetal neocortex. Here, we show that CUX2 protein is expressed in transient compartments of developing neocortical anlage during the main fetal phases of neocortical laminar development in human brain. During the early fetal phase when neurons of the upper cortical layers are still radially migrating to reach their final place in the cortical anlage, CUX2 was expressed in the marginal zone (MZ), deep cortical plate, and pre-subplate. During midgestation, CUX2 was still expressed in the migrating upper cortical neurons as well as in the subplate (SP) and MZ neurons. At the term age, CUX2 was expressed in the gyral white matter along with its expected expression in the upper layer neurons. In sum, CUX2 was expressed in migratory neurons of prospective superficial layers and in the diverse subpopulation of transient postmigratory SP and MZ neurons. Therefore, our findings indicate that CUX2 is a novel marker of distinct transient, but critical histogenetic events during corticogenesis. Given the Cux2 functions reported in animal models, our data further suggest that the expression of CUX2 in postmigratory SP and MZ neurons is associated with their unique dendritic and synaptogenesis characteristics.

scholarly journals Cortical upper layer neurons derive from the subventricular zone as indicated bySvet1gene expression

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 1983-1993 ◽  
Author(s):  
Victor Tarabykin ◽  
Anastassia Stoykova ◽  
Natalia Usman ◽  
Peter Gruss
Keyword(s):  
Cerebral Cortex ◽  
Molecular Markers ◽  
Cortical Neurons ◽  
Ventricular Zone ◽  
Underlying Mechanism ◽  
Cdna Libraries ◽  
Cortical Plate ◽  
Cortical Layers ◽  
Proliferating Cells ◽  
Expression Domain

The cerebral cortex is composed of a large variety of different neuron types. All cortical neurons, except some interneurons, are born in two proliferative zones, the cortical ventricular (VZ) and subventricular (SVZ) zones. The relative contribution of both proliferative zones to the generation of the diversity of the cortical neurons is not well understood. To further dissect the underlying mechanism, molecular markers specific for the SVZ are required. Towards this end we performed a subtraction of cDNA libraries, generated from E15.5 and E18.5 mouse cerebral cortex. A novel cDNA, Svet1, was cloned which was specifically expressed in the proliferating cells of the SVZ but not the VZ. The VZ is marked by the expression of the Otx1 gene. Later in development, Svet1 and Otx1 were expressed in subsets of cells of upper (II-IV) and deep (V-VI) layers, respectively. In the reeler cortex, where the layers are inverted, Svet1 and Otx1 label precursors of the upper and deeper layers, respectively, in their new location. Interestingly, in the Pax6/small eye mutant, Svet1 activity was abolished in the SVZ and in the upper part of the cortical plate while the Otx1 expression domain remained unchanged. Therefore, using Svet1 and Otx1 as cell-type-specific molecular markers for the upper and deep cortical layers we conclude that the Sey mutation affects predominantly the differentiation of the SVZ cells that fail to migrate into the cortical plate. The abnormality of the SVZ coincides with the absence of upper layer cells in the cortex. Taken together our data suggest that while the specification of deep cortical layers occurs in the ventricular zone, the SVZ is important for the proper specification of upper layers.

scholarly journals From compartments to gene loops: Functions of the 3D genome in the human brain

2021 ◽  
Author(s):  
Samir Rahman ◽  
Pengfei Dong ◽  
Pasha Apontes ◽  
Michael B. Fernando ◽  
Kayla G. Townsley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Neural Development ◽  
Cortical Neurons ◽  
Regulation Of Gene Expression ◽  
Cortical Plate ◽  
3D Genome ◽  
Prefrontal Cortical ◽  
Loop Domains ◽  
The Relationship

The 3D genome plays a key role in the regulation of gene expression. However, little is known about the spatiotemporal organization of chromatin during human brain development. We investigated the 3D genome in human fetal cortical plate and in adult prefrontal cortical neurons and glia. We found that neurons have weaker compartments than glia that emerge during fetal development. Furthermore, neurons form loop domains whereas glia form compartment domains. We show through CRISPRi on CNTNAP2 that transcription is coupled to loop domain insulation. Gene regulation during neural development involves increased use of enhancer-promoter and repressor-promoter loops. Finally, transcription is associated with gene loops. Altogether, we provide novel insights into the relationship between gene expression and different scales of chromatin organization in the human brain.

scholarly journals Differential expression levels of Sox9 in early neocortical radial glial cells regulate the decision between stem cell maintenance and differentiation

2020 ◽  
Author(s):  
Jaime Fabra-Beser ◽  
Jessica Alves Medeiros de Araujo ◽  
Diego Marques-Coelho ◽  
Loyal A. Goff ◽  
Ulrich Müller ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Progenitor Cells ◽  
Differential Expression ◽  
Cortical Neurons ◽  
Expression Patterns ◽  
Neuronal Cell ◽  
Cell Types ◽  
Molecular Signature ◽  
Projection Neurons ◽  
Radial Glial

ABSTRACTRadial glial progenitor cells (RGCs) in the dorsal forebrain directly or indirectly produce excitatory projection neurons and macroglia of the neocortex. Recent evidence shows that the pool of RGCs is more heterogeneous than originally thought and that progenitor subpopulations can generate particular neuronal cell types. Using single cell RNA sequencing, we have studied gene expression patterns of two subtypes of RGCs that differ in their neurogenic behavior. One progenitor type rapidly produces postmitotic neurons, whereas the second progenitor remains relatively quiescence before generating neurons. We have identified candidate genes that are differentially expressed between these RGCs progenitor subtypes, including the transcription factor Sox9. Using in utero electroporation, we demonstrate that elevated Sox9 expression in progenitors prevents RGC division and leads to the generation of upper-layer cortical neurons from these progenitors at later ages. Our data thus reveal molecular differences between cortical progenitors with different neurogenic behavior and indicates that Sox9 is critical for the maintenance of RGCs to regulate the generation of upper layer neurons.SIGNIFICANCE STATEMENTThe existence of heterogeneity in the pool of RGCs and its relationship with the generation of cellular diversity in the cerebral cortex has been an interesting topic of debate for many years. Here we describe the existence of a subpopulation of RGCs with reduced neurogenic behavior at early embryonic ages presenting a particular molecular signature. This molecular signature consists of differential expression of some genes including the transcription factor Sox9, found to be a specific master regulator of this subpopulation of progenitor cells. Functional experiments perturbing Sox9 expression’s levels reveal its instructive role in the regulation of the neurogenic behavior of RGCs and its relationship with the generation of upper layer projection neurons at later ages.

scholarly journals Circuits in the absence of cortical layers: increased callosal connectivity in reeler mice revealed by brain-wide input mapping of VIP neurons in barrel cortex

2020 ◽  
Author(s):  
Georg Hafner ◽  
Julien Guy ◽  
Mirko Witte ◽  
Pavel Truschow ◽  
Alina Rüppel ◽  
...  
Keyword(s):  
Long Range ◽  
Cortical Neurons ◽  
Barrel Cortex ◽  
Projection Neurons ◽  
Cortical Layers ◽  
Subcortical Structures ◽  
Virus Tracing ◽  
Cortical Inputs ◽  
Callosal Projection ◽  
To Receive

ABSTRACTThe neocortex is composed of layers. Whether layers constitute an essential framework for the formation of functional circuits is not well understood. We investigated if neurons require the layer organization to be embedded into brain-wide circuits using the reeler mouse. This mutant is characterized by a migration deficit of cortical neurons so that no layers are formed. Still, neurons retain their properties and reeler mice show little cognitive impairment. We focused on VIP neurons because they are known to receive strong long-range inputs and have a typical laminar bias towards upper layers. In reeler these neurons are more distributed across the cortex. We mapped the brain-wide inputs of VIP neurons in barrel cortex of wildtype and reeler mice with rabies virus tracing. Innervation by subcortical inputs was not altered in reeler, in contrast to the cortical circuitry. Numbers of long-range ipsilateral cortical inputs were reduced in reeler, while contralateral inputs were strongly increased. Reeler mice had more callosal projection neurons. Hence, the corpus callosum was larger in reeler as shown by structural imaging. We argue that in the absence of cortical layers, circuits with subcortical structures are maintained but cortical neurons establish a different network capable to preserve cognitive functions.

scholarly journals Chronic and Acute Manipulation of Cortical Glutamate Transmission Induces Structural and Synaptic Changes in Co-cultured Striatal Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Naila Kuhlmann ◽  
Miriam Wagner Valladolid ◽  
Lucía Quesada-Ramírez ◽  
Matthew J. Farrer ◽  
Austen J. Milnerwood
Keyword(s):  
Nmda Receptor ◽  
Cortical Neurons ◽  
Synapse Formation ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Projection Neurons ◽  
Spine Density ◽  
Striatal Neurons ◽  
Synapse Plasticity

In contrast to the prenatal topographic development of sensory cortices, striatal circuit organization is slow and requires the functional maturation of cortical and thalamic excitatory inputs throughout the first postnatal month. While mechanisms regulating synapse development and plasticity are quite well described at excitatory synapses of glutamatergic neurons in the neocortex, comparatively little is known of how this translates to glutamate synapses onto GABAergic neurons in the striatum. Here we investigate excitatory striatal synapse plasticity in an in vitro system, where glutamate can be studied in isolation from dopamine and other neuromodulators. We examined pre-and post-synaptic structural and functional plasticity in GABAergic striatal spiny projection neurons (SPNs), co-cultured with glutamatergic cortical neurons. After synapse formation, medium-term (24 h) TTX silencing increased the density of filopodia, and modestly decreased dendritic spine density, when assayed at 21 days in vitro (DIV). Spine reductions appeared to require residual spontaneous activation of ionotropic glutamate receptors. Conversely, chronic (14 days) TTX silencing markedly reduced spine density without any observed increase in filopodia density. Time-dependent, biphasic changes to the presynaptic marker Synapsin-1 were also observed, independent of residual spontaneous activity. Acute silencing (3 h) did not affect presynaptic markers or postsynaptic structures. To induce rapid, activity-dependent plasticity in striatal neurons, a chemical NMDA receptor-dependent “long-term potentiation (LTP)” paradigm was employed. Within 30 min, this increased spine and GluA1 cluster densities, and the percentage of spines containing GluA1 clusters, without altering the presynaptic signal. The results demonstrate that the growth and pruning of dendritic protrusions is an active process, requiring glutamate receptor activity in striatal projection neurons. Furthermore, NMDA receptor activation is sufficient to drive glutamatergic structural plasticity in SPNs, in the absence of dopamine or other neuromodulators.

scholarly journals Terminal neuron localization to the upper cortical plate is controlled by the transcription factor NEUROD2

2019 ◽  
Author(s):  
Gizem Guzelsoy ◽  
Cansu Akkaya ◽  
Dila Atak ◽  
Cory D. Dunn ◽  
Alkan Kabakcioglu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Cellular Localization ◽  
Morphological Properties ◽  
Cortical Plate ◽  
Strong Increase ◽  
Migration Process ◽  
Proliferative Zone ◽  
New Genes

AbstractExcitatory neurons of the mammalian cerebral cortex are organized into six functional layers characterized by unique patterns of connectivity, as well as distinctive physiological and morphological properties. Cortical layers appear after a highly regulated migration process in which cells move from the deeper, proliferative zone toward the superficial layers. Importantly, defects in this radial migration process have been implicated in neurodevelopmental and psychiatric diseases. Here we report that during the final stages of migration, transcription factor Neurogenic Differentiation 2 (Neurod2) contributes to terminal cellular localization within the cortical plate. In mice, in utero knockdown of Neurod2 results in reduced numbers of neurons localized to the uppermost region of the developing cortex, also termed the primitive cortical zone. Our ChIP-Seq and RNA-Seq analyses of genes regulated by NEUROD2 in the developing cortex identify a number of key target genes with known roles in Reelin signaling, a critical regulator of neuronal migration. Our focused analysis of regulation of the Reln gene, encoding the extracellular ligand REELIN, uncovers NEUROD2 binding to conserved E-box elements in multiple introns. Furthermore, we demonstrate that knockdown of NEUROD2 in primary cortical neurons results in a strong increase in Reln gene expression at the mRNA level, as well as a slight upregulation at the protein level. These data reveal a new role for NEUROD2 during the late stages of neuronal migration, and our analysis of its genomic targets offer new genes with potential roles in cortical lamination.

scholarly journals Loss of Dmrt5 Affects the Formation of the Subplate and Early Corticogenesis

2019 ◽  
Vol 30 (5) ◽  
pp. 3296-3312 ◽  
Author(s):  
Leslie Ratié ◽  
Elodie Desmaris ◽  
Fernando García-Moreno ◽  
Anna Hoerder-Suabedissen ◽  
Alexandra Kelman ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Marginal Zone ◽  
Cortical Plate ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
Time Sensitivity ◽  
Proliferation And Differentiation ◽  
Cortical Patterning ◽  
Summary Statement ◽  
And Migration

Abstract Dmrt5 (Dmrta2) and Dmrt3 are key regulators of cortical patterning and progenitor proliferation and differentiation. In this study, we show an altered apical to intermediate progenitor transition, with a delay in SP neurogenesis and premature birth of Ctip2+ cortical neurons in Dmrt5−/− mice. In addition to the cortical progenitors, DMRT5 protein appears present in postmitotic subplate (SP) and marginal zone neurons together with some migrating cortical neurons. We observed the altered split of preplate and the reduced SP and disturbed radial migration of cortical neurons into cortical plate in Dmrt5−/− brains and demonstrated an increase in the proportion of multipolar cells in primary neuronal cultures from Dmrt5−/− embryonic brains. Dmrt5 affects cortical development with specific time sensitivity that we described in two conditional mice with slightly different deletion time. We only observed a transient SP phenotype at E15.5, but not by E18.5 after early (Dmrt5lox/lox;Emx1Cre), but not late (Dmrt5lox/lox;NestinCre) deletion of Dmrt5. SP was less disturbed in Dmrt5lox/lox;Emx1Cre and Dmrt3−/− brains than in Dmrt5−/− and affects dorsomedial cortex more than lateral and caudal cortex. Our study demonstrates a novel function of Dmrt5 in the regulation of early SP formation and radial cortical neuron migration. Summary Statement Our study demonstrates a novel function of Dmrt5 in regulating marginal zone and subplate formation and migration of cortical neurons to cortical plate.

scholarly journals Terminal neuron localization to the upper cortical plate is controlled by the transcription factor NEUROD2

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gizem Guzelsoy ◽  
Cansu Akkaya ◽  
Dila Atak ◽  
Cory D. Dunn ◽  
Alkan Kabakcioglu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Cellular Localization ◽  
Morphological Properties ◽  
Cortical Plate ◽  
Strong Increase ◽  
Migration Process ◽  
Proliferative Zone ◽  
New Genes

AbstractExcitatory neurons of the mammalian cerebral cortex are organized into six functional layers characterized by unique patterns of connectivity, as well as distinctive physiological and morphological properties. Cortical layers appear after a highly regulated migration process in which cells move from the deeper, proliferative zone toward the superficial layers. Importantly, defects in this radial migration process have been implicated in neurodevelopmental and psychiatric diseases. Here we report that during the final stages of migration, transcription factor Neurogenic Differentiation 2 (Neurod2) contributes to terminal cellular localization within the cortical plate. In mice, in utero knockdown of Neurod2 resulted in reduced numbers of neurons localized to the uppermost region of the developing cortex, also termed the primitive cortical zone. Our ChIP-Seq and RNA-Seq analyses of genes regulated by NEUROD2 in the developing cortex identified a number of key target genes with known roles in Reelin signaling, a critical regulator of neuronal migration. Our focused analysis of regulation of the Reln gene, encoding the extracellular ligand REELIN, uncovered NEUROD2 binding to conserved E-box elements in multiple introns. Furthermore, we demonstrate that knockdown of NEUROD2 in primary cortical neurons resulted in a strong increase in Reln gene expression at the mRNA level, as well as a slight upregulation at the protein level. These data reveal a new role for NEUROD2 during the late stages of neuronal migration, and our analysis of its genomic targets offers new genes with potential roles in cortical lamination.

scholarly journals Reelin Signals through Phosphatidylinositol 3-Kinase and Akt To Control Cortical Development and through mTor To Regulate Dendritic Growth

2007 ◽  
Vol 27 (20) ◽  
pp. 7113-7124 ◽  
Author(s):  
Yves Jossin ◽  
André M. Goffinet
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Matrix Protein ◽  
Glycogen Synthase ◽  
Extracellular Matrix Protein ◽  
Cortical Plate ◽  
Target Cells ◽  
Neuronal Cultures ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

ABSTRACT Reelin is an extracellular matrix protein with various functions during development and in the mature brain. It activates different signaling cascades in target cells, one of which is the phosphatidylinositol 3-kinase (PI3K) pathway, which we investigated further using pathway inhibitors and in vitro brain slice and neuronal cultures. We show that the mTor (mammalian target of rapamycin)-S6K1 (S6 kinase 1) pathway is activated by Reelin and that this depends on Dab1 (Disabled-1) phosphorylation and activation of PI3K and Akt (protein kinase B). PI3K and Akt are required for the effects of Reelin on the organization of the cortical plate, but their downstream partners mTor and glycogen synthase kinase 3β (GSK3β) are not. On the other hand, mTor, but not GSK3β, mediates the effects of Reelin on the growth and branching of dendrites of hippocampal neurons. In addition, PI3K fosters radial migration of cortical neurons through the intermediate zone, an effect that is independent of Reelin and Akt.

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