scholarly journals Involvement of Netrins and Their Receptors in Neuronal Migration in the Cerebral Cortex

2021 ◽  
Vol 8 ◽  
Author(s):  
Satoru Yamagishi ◽  
Yuki Bando ◽  
Kohji Sato
Keyword(s):  
Neuronal Migration ◽  
Cortical Neurons ◽  
Intracellular Signaling ◽  
Ventricular Zone ◽  
Genetic Disorders ◽  
Cortical Plate ◽  
Ganglionic Eminence ◽  
Deleted In Colorectal Cancer ◽  
Guidance Molecules ◽  
Extracellular Molecules

In mammals, excitatory cortical neurons develop from the proliferative epithelium and progenitor cells in the ventricular zone and subventricular zone, and migrate radially to the cortical plate, whereas inhibitory GABAergic interneurons are born in the ganglionic eminence and migrate tangentially. The migration of newly born cortical neurons is tightly regulated by both extracellular and intracellular signaling to ensure proper positioning and projections. Non-cell-autonomous extracellular molecules, such as growth factors, axon guidance molecules, extracellular matrix, and other ligands, play a role in cortical migration, either by acting as attractants or repellents. In this article, we review the guidance molecules that act as cell–cell recognition molecules for the regulation of neuronal migration, with a focus on netrin family proteins, their receptors, and related molecules, including neogenin, repulsive guidance molecules (RGMs), Down syndrome cell adhesion molecule (DSCAM), fibronectin leucine-rich repeat transmembrane proteins (FLRTs), and draxin. Netrin proteins induce attractive and repulsive signals depending on their receptors. For example, binding of netrin-1 to deleted in colorectal cancer (DCC), possibly together with Unc5, repels migrating GABAergic neurons from the ventricular zone of the ganglionic eminence, whereas binding to α3β1 integrin promotes cortical interneuron migration. Human genetic disorders associated with these and related guidance molecules, such as congenital mirror movements, schizophrenia, and bipolar disorder, are also discussed.

scholarly journals An absence of lamin B1 in migrating neurons causes nuclear membrane ruptures and cell death

2019 ◽  
Vol 116 (51) ◽  
pp. 25870-25879 ◽  
Author(s):  
Natalie Y. Chen ◽  
Ye Yang ◽  
Thomas A. Weston ◽  
Jason N. Belling ◽  
Patrick Heizer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Nuclear Membrane ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Nuclear Translocation ◽  
Neuronal Survival ◽  
Ventricular Zone ◽  
Cortical Plate ◽  
Lamin B1

Deficiencies in either lamin B1 or lamin B2 cause both defective migration of cortical neurons in the developing brain and reduced neuronal survival. The neuronal migration abnormality is explained by a weakened nuclear lamina that interferes with nucleokinesis, a nuclear translocation process required for neuronal migration. In contrast, the explanation for impaired neuronal survival is poorly understood. We hypothesized that the forces imparted on the nucleus during neuronal migration result in nuclear membrane (NM) ruptures, causing interspersion of nuclear and cytoplasmic contents—and ultimately cell death. To test this hypothesis, we bredLmnb1-deficient mice that express a nuclear-localized fluorescentCrereporter. Migrating neurons within the cortical plate of E18.5Lmnb1-deficient embryos exhibited NM ruptures, evident by the escape of the nuclear-localized reporter into the cytoplasm and NM discontinuities by electron microscopy. The NM ruptures were accompanied by DNA damage and cell death. The NM ruptures were not observed in nonmigrating cells within the ventricular zone. NM ruptures, DNA damage, and cell death were also observed in culturedLmnb1−/−andLmnb2−/−neurons as they migrated away from neurospheres. To test whether mechanical forces on the cell nucleus are relevant to NM ruptures in migrating neurons, we examined culturedLmnb1−/−neurons when exposed to external constrictive forces (migration into a field of tightly spaced silicon pillars). As the cells entered the field of pillars, there were frequent NM ruptures, accompanied by DNA damage and cell death.

scholarly journals Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex

2015 ◽  
Vol 37 (2) ◽  
pp. 131-141 ◽  
Author(s):  
Shuhong Qiao ◽  
Ramin Homayouni
Keyword(s):  
Brain Development ◽  
Cortical Neurons ◽  
Ventricular Zone ◽  
Physiological Role ◽  
Immunohistochemical Analysis ◽  
Superficial Layer ◽  
Tumor Formation ◽  
Intermediate Zone ◽  
Cortical Plate ◽  
Integrin Signaling

Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase-activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP-knockdown (KD) mouse model created by retroviral insertion of a LacZ-encoding gene-trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunohistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. Bromodeoxyuridine birth dating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II-IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP-KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition from multipolar to bipolar morphology in migrating postmitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of the cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP-KD brains. We found that Dab2IP-KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a subpopulation of later-born (layers II-IV) neurons, likely through the regulation of Rap1 and integrin signaling.

Changing Properties of GABAA Receptor–Mediated Signaling During Early Neocortical Development

1999 ◽  
Vol 82 (2) ◽  
pp. 570-583 ◽  
Author(s):  
David F. Owens ◽  
Xiaolin Liu ◽  
Arnold R. Kriegstein
Keyword(s):  
Action Potential ◽  
Cortical Neurons ◽  
Ventricular Zone ◽  
Receptor Activation ◽  
Brain Regions ◽  
Functional Change ◽  
Precursor Cells ◽  
Synaptic Activity ◽  
Cortical Plate ◽  
Early Maturation

Evidence from several brain regions suggests γ-aminobutyric acid (GABA) can exert a trophic influence during development, expanding the role of this amino acid beyond its function as an inhibitory neurotransmitter. Proliferating precursor cells in the neocortical ventricular zone (VZ) express functional GABAA receptors as do immature postmigratory neurons in the developing cortical plate (CP); however, GABAA receptor properties in these distinct cell populations have not been compared. Using electrophysiological techniques in embryonic and early postnatal neocortex, we find that GABAA receptors expressed by VZ cells have a higher apparent affinity for GABA and are relatively insensitive to receptor desensitization compared with neurons in the CP. GABA-induced current magnitude increases with maturation with the smallest responses found in recordings from precursor cells in the VZ. No evidence was found that GABAA receptors on VZ cells are activated synaptically, consistent with previous data suggesting that these receptors are activated in a paracrine fashion by nonsynaptically released ligand. After neurons are born and migrate to the CP, they begin to demonstrate spontaneous synaptic activity, the majority of which is GABAA mediated. These spontaneous GABAA postsynaptic currents (sPSCs) first were detected at embryonic day 18 (E18). At birth, ∼50% of recordings from cortical neurons demonstrated GABAA-mediated sPSCs, and this value increased with age. GABAA-mediated sPSCs were action potential dependent and arose from local GABAergic interneurons. GABA application could evoke action potential–dependent PSCs in neonatal cortical neurons, suggesting that during the first few postnatal days, GABA can act as an excitatory neurotransmitter. Finally, N-methyl-d-aspartate (NMDA)- but not non-NMDA-mediated sPSCs were also present in early postnatal neurons. These events were not observed in cells voltage clamped at negative holding potentials (−60 to −70 mV) but were evident when the holding potential was set at positive values (+30 to +60 mV). Together these results provide evidence for the early maturation of GABAergic communication in the neocortex and a functional change in GABAA-receptor properties between precursor cells and early postmitotic neurons. The change in GABAA-receptor properties may reflect the shift from paracrine to synaptic receptor activation.

Tangential migration of neurons in the developing cerebral cortex

Development ◽  
1995 ◽  
Vol 121 (7) ◽  
pp. 2165-2176 ◽  
Author(s):  
N.A. O'Rourke ◽  
D.P. Sullivan ◽  
C.E. Kaznowski ◽  
A.A. Jacobs ◽  
S.K. McConnell
Keyword(s):  
Cerebral Cortex ◽  
Neuronal Migration ◽  
Ventricular Zone ◽  
Brain Slices ◽  
Cortical Plate ◽  
Tangential Migration ◽  
Cortical Regions ◽  
Intact Cortex ◽  
Migrating Cells

The mammalian cerebral cortex is divided into functionally distinct areas. Although radial patterns of neuronal migration have been thought to be essential for patterning these areas, direct observation of migrating cells in cortical brain slices has revealed that cells follow both radial and nonradial pathways as they travel from their sites of origin in the ventricular zone out to their destinations in the cortical plate (O'Rourke, N.A., Dailey, M.E., Smith, S.J. and McConnell, S.K. (1992) Science 258, 299–302). These findings suggested that neurons may not be confined to radial migratory pathways in vivo. Here, we have examined the patterns of neuronal migration in the intact cortex. Analysis of the orientations of [3H]thymidine-labeled migrating cells suggests that nonradial migration is equally common in brain slices and the intact cortex and that it increases during neurogenesis. Additionally, cells appear to follow nonradial trajectories at all levels of the developing cerebral wall, suggesting that tangential migration may be more prevalent than previously suspected from the imaging studies. Immunostaining with neuron-specific antibodies revealed that many tangentially migrating cells are young neurons. These results suggest that tangential migration in the intact cortex plays a pivotal role in the tangential dispersion of clonally related cells revealed by retroviral lineage studies (Walsh, C. and Cepko, C. L. (1992) Science 255, 434–440). Finally, we examined possible substrata for nonradial migration in dorsal cortical regions where the majority of glia extend radially. Using confocal and electron microscopy, we found that nonradially oriented cells run perpendicular to glial processes and make glancing contacts with them along their leading processes. Thus, if nonradial cells utilize glia as a migratory substratum they must glide across one glial fiber to another. Examination of the relationships between migratory cells and axons revealed axonal contacts with both radial and nonradial cells. These results suggest that nonradial cells use strategies and substrata for migration that differ from those employed by radial cells.

scholarly journals Phosphorylation of Focal Adhesion Kinase at Tyr925: Role in Glia-Dependent and Independent Migration Through Regulating Cofilin and N-Cadherin

2021 ◽  
Author(s):  
Lingzhen Song ◽  
Shanting Zhao ◽  
Michael Frotscher ◽  
Xuejun Chai
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Ventricular Zone ◽  
Focal Adhesions ◽  
Developing Neocortex ◽  
Reelin Signaling ◽  
Highly Correlated

Abstract The adult neocortex is a six-layered structure, consisting of nearly continuous layers of neurons that are generated with large temporal diversity. During development, cortical neurons originating from the ventricular zone migrate towards the Reelin-containing marginal zone in an inside-out arrangement. Focal adhesion kinase (FAK), one tyrosine kinase localizing to focal adhesions, has been shown to be activated by Src, an important downstream molecule of Reelin signaling, at tyrosine 925 (Y925). Up to date, the precise molecular mechanisms of FAK and its phosphorylation at Y925 during neuronal migration are still unclear. Combining in utero electroporation with immunohistochemistry and live imaging, we examined the function of FAK in regulating neuronal migration. We show that phosphorylated FAK is colocalized with Reelin positive cells in the developing neocortex and hippocampus. Phosphorylation of FAK at Y925 is significantly reduced in reeler mice. Overexpression and dephosphorylation of FAK impair locomotion and translocation, resulting in migration inhibition and dislocation of both late-born and early-born neurons. These migration defects are highly correlated to the function of FAK in regulating cofilin phosphorylation and N-Cadherin expression, both are involved in Reelin signaling pathway. Thus, phosphorylation of focal adhesion kinase at Y925 is crucial for both glia-dependent and independent neuronal migration.

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 Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex

2018 ◽  
Vol 29 (9) ◽  
pp. 3738-3751
Author(s):  
Keiko Nakanishi ◽  
Hiroyuki Niida ◽  
Hidenori Tabata ◽  
Tsuyoshi Ito ◽  
Yuki Hori ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Cortical Neurons ◽  
Hippocampal Neurons ◽  
Average Length ◽  
Time Lapse ◽  
Cortical Plate ◽  
Birth Date ◽  
Presynaptic Vesicle ◽  
Different Genetic Background ◽  
Time Lapse Imaging

Abstract SAD kinases regulate presynaptic vesicle clustering and neuronal polarization. A previous report demonstrated that Sada−/− and Sadb−/− double-mutant mice showed perinatal lethality with a severe defect in axon/dendrite differentiation, but their single mutants did not. These results indicated that they were functionally redundant. Surprisingly, we show that on a C57BL/6N background, SAD-A is essential for cortical development whereas SAD-B is dispensable. Sada−/− mice died within a few days after birth. Their cortical lamination pattern was disorganized and radial migration of cortical neurons was perturbed. Birth date analyses with BrdU and in utero electroporation using pCAG-EGFP vector showed a delayed migration of cortical neurons to the pial surface in Sada−/− mice. Time-lapse imaging of these mice confirmed slow migration velocity in the cortical plate. While the neurites of hippocampal neurons in Sada−/− mice could ultimately differentiate in culture to form axons and dendrites, the average length of their axons was shorter than that of the wild type. Thus, analysis on a different genetic background than that used initially revealed a nonredundant role for SAD-A in neuronal migration and differentiation.

scholarly journals Septin 14 Is Involved in Cortical Neuronal Migration via Interaction with Septin 4

2010 ◽  
Vol 21 (8) ◽  
pp. 1324-1334 ◽  
Author(s):  
Tomoyasu Shinoda ◽  
Hidenori Ito ◽  
Kaori Sudo ◽  
Ikuko Iwamoto ◽  
Rika Morishita ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Neuronal Migration ◽  
Cortical Neurons ◽  
Neuronal Development ◽  
Cell Cycle Control ◽  
Coiled Coil ◽  
Cortical Plate ◽  
Process Formation ◽  
Biochemical Analyses

Septins are a family of conserved guanosine triphosphate/guanosine diphosphate-binding proteins implicated in a variety of cellular functions such as cell cycle control and cytokinesis. Although several members of septin family, including Septin 14 (Sept14), are abundantly expressed in nervous tissues, little is known about their physiological functions, especially in neuronal development. Here, we report that Sept14 is strongly expressed in the cortical plate of developing cerebral cortex. Knockdown experiments by using the method of in utero electroporation showed that reduction of Sept14 caused inhibition of cortical neuronal migration. Whereas cDNA encoding RNA interference-resistant Sept14 rescued the migration defect, the C-terminal deletion mutant of Sept14 did not. Biochemical analyses revealed that C-terminal coiled-coil region of Sept14 interacts with Septin 4 (Sept4). Knockdown experiments showed that Sept4 is also involved in cortical neuronal migration in vivo. In addition, knockdown of Sept14 or Sept4 inhibited leading process formation in migrating cortical neurons. These results suggest that Sept14 is involved in neuronal migration in cerebral cortex via interaction with Sept4.

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 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.

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