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The 14-3-3 family comprises multifunctional proteins that play a role in neurogenesis, neuronal migration, neuronal differentiation, synaptogenesis and dopamine synthesis. 14-3-3 members function as adaptor proteins and impact a wide variety of cellular and physiological processes involved in the pathophysiology of neurological disorders. Schizophrenia is a psychiatric disorder and knowledge about its pathophysiology is still limited. 14-3-3 have been proven to be linked with the dopaminergic, glutamatergic and neurodevelopmental hypotheses of schizophrenia. Further, research using genetic models has demonstrated the role played by 14-3-3 proteins in neurodevelopment and neuronal circuits, however a more integrative and comprehensive approach is needed for a better understanding of their role in schizophrenia. For instance, we still lack an integrated assessment of the processes affected by 14-3-3 proteins in the dopaminergic and glutamatergic systems. In this context, it is also paramount to understand their involvement in the biology of brain cells other than neurons. Here, we present previous and recent research that has led to our current understanding of the roles 14-3-3 proteins play in brain development and schizophrenia, perform an assessment of their functional protein association network and discuss the use of protein-protein interaction modulators to target 14-3-3 as a potential therapeutic strategy.

Environmental chemical and physical cues dynamically interact with migrating neurons and sprouting axons, and in particular, the gradients of environmental cues are regarded as one of the factors intimately involved in the neuronal movement. Since a growth cone was first described by Cajal, more than one century ago, chemical gradients have been suggested as one of the mechanisms by which the neurons determine proper paths and destinations. However, the gradients of physical cues, such as stiffness and topography, which also interact constantly with the neurons and their axons as a component of the extracellular environments, have rarely been noted regarding the guidance of neurons, despite their gradually increasingly reported influences in the case of nonneuronal-cell migration. In this review, we discuss chemical (i.e., chemo- and hapto-) and physical (i.e., duro-) taxis phenomena on the movement of neurons including axonal elongation. In addition, we suggest topotaxis, the most recently proposed physical-taxis phenomenon, as another potential mechanism in the neuronal movement, based on the reports of neuronal recognition of and responses to nanotopography.

The highly organized laminar structure of the mammalian brain is dependent on successful neuronal migration, and migration deficits can cause lissencephaly and behavioral and cognitive defects. Here, we investigated the contribution of neuronal migration dysregulation to anesthesia-induced neurotoxicity in the fetal brain. Pregnant C57BL/6 mice at embryonic day 14.5 received 2.5% sevoflurane daily for two days. Cortical neuron migration and axon lengths were evaluated using GFP immunostaining. Morris water maze tests were performed to assess the effects of sevoflurane exposure on spatial memory in offspring. We found that sevoflurane exposure decreased axon length and caused cognitive defects in young mice. RNA sequencing revealed that these defects were associated with reduced neuro-oncological ventral antigen 2 (Nova2) expression. In utero electroporation experiments using Nova2 shRNA recapitulated this finding. Nova2 shRNA inhibited neuronal migration and decreased axon lengths. Finally, we found that Netrin-1/Deleted in Colorectal Cancer (Dcc) proteins acted downstream of Nova2 to suppresses neuronal migration. These findings describe a novel mechanism by which prenatal anesthesia exposure affects embryonic neural development and postnatal behavior.

Summary The neural stem cells (NSCs) residing in the olfactory epithelium (OE) regenerate damaged olfactory sensory neurons throughout adulthood. The accessibility and availability of these NSCs in living individuals, including humans, makes them a promising candidate for harvesting their potential for cell replacement therapies. However, this requires an in-depth understanding of their developmental potential after grafting. Here, we investigated the developmental potential and plasticity of mouse OE-derived NSCs after grafting into the adult subventricular zone (SVZ) neurogenic niche. Our results showed that OE-derived NSCs integrate and proliferate just like endogenous SVZ stem cells, migrate with similar dynamics as endogenous neuroblasts toward the olfactory bulb, and mature and acquire similar electrophysiological properties as endogenous adult-born bulbar interneurons. These results reveal the developmental potential and plasticity of OE-derived NSCs in vivo and show that they can respond to heterotopic neurogenic cues to adapt their phenotype and become functional neurons in ectopic brain regions., Graphical Abstract, Highlights • OE-derived NSCs integrate in the SVZ after heterotopic transplantation • OE-derived NSCs respond to SVZ niche factors and change their developmental program • The development of OE-derived and SVZ NSCs are indistinguishable • OE-derived NSCs grafted into the SVZ become functional bulbar interneurons, In this article, Saghatelyan and colleagues show that olfactory epithelium-derived neural stem cells adapt their developmental program in response to heterotopic neurogenic niche factors after grafting in vivo. They migrate and differentiate into ectopic brain region neurons that are indistinguishable in their morpho-functional properties from endogenous adult-born neurons.

The amygdala is a hyperspecialized brain region composed of strongly inter- and intraconnected nuclei involved in emotional learning and behavior. The cellular heterogeneity of the amygdalar nuclei has complicated straightforward conclusions on their developmental origin, and even resulted in contradictory data. Recently, the concentric ring theory of the pallium and the radial histogenetic model of the pallial amygdala have cleared up several uncertainties that plagued previous models of amygdalar development. Here, we provide an extensive overview on the developmental origin of the nuclei of the amygdaloid complex. Starting from older gene expression data, transplantation and lineage tracing studies, we systematically summarize and reinterpret previous findings in light of the novel perspectives on amygdalar development. In addition, migratory routes that these cells take on their way to the amygdala are explored, and known transcription factors and guidance cues that seemingly drive these cells toward the amygdala are emphasized. We propose some future directions for research on amygdalar development and highlight that a better understanding of its development could prove critical for the treatment of several neurodevelopmental and neuropsychiatric disorders. ispartof: Frontiers In Neuroanatomy vol:15 ispartof: location:Switzerland status: Published online

Radial neuron migration in the developing cerebral cortex is a complex journey, starting in the germinal zones and ending in the cortical plate. In mice, migratory distances can reach several hundreds of microns, or millimeters in humans. Along the migratory path, radially migrating neurons slither through cellularly dense and complex territories before they reach their final destination in the cortical plate. This task is facilitated by radial glia, the neural stem cells of the developing cortex. Indeed, radial glia have a unique bipolar morphology, enabling them to serve as guides for neuronal migration. The key guiding structure of radial glia is the basal process, which traverses the entire thickness of the developing cortex. Neurons recognize the basal process as their guide and maintain physical interactions with this structure until the end of migration. Thus, the radial glia basal process plays a key role during radial migration. In this review, we highlight the pathways enabling neuron-basal process interactions during migration, as well as the known mechanisms regulating the morphology of the radial glia basal process. Throughout, we describe how dysregulation of these interactions and of basal process morphology can have profound effects on cortical development, and therefore lead to neurodevelopmental diseases.

As neurons are often born at positions different than where they ultimately function, neuronal migration is key to ensure successful nervous system development. Radial migration during which neurons featuring unipolar and bipolar morphology, employ pre-existing processes or underlying cells for directional guidance, is the most well explored neuronal migration mode. However, how neurons that display multipolar morphology, without such processes, move through highly crowded tissue environments towards their final positions remains elusive. To understand this, we here investigated multipolar migration of horizontal cells in the zebrafish retina. We found that horizontal cells tailor their movements to the environmental spatial constraints of the crowded retina, by featuring several characteristics of amoeboid migration. These include cell and nucleus shape changes, and persistent rearward polarization of stable F-actin, which enable horizontal cells to successfully move through the crowded retina. Interference with the organization of the developing retina by changing nuclear properties or overall tissue architecture, hampers efficient horizontal cell migration and layer formation. Thus, cell-tissue interplay is crucial for efficient migration of horizontal cells in the retina. In view of high proportion of multipolar neurons, the here uncovered ameboid-like neuronal migration mode might also be crucial in other areas of the developing brain.

Cell polarity is fundamentally important for understanding brain development. Here, we hypothesize that the inheritance and flexibility of cell polarity during neocortex development could be implicated in neocortical evolutionary expansion. Molecular and morphological features of cell polarity may be inherited from one type of progenitor cell to the other and finally transmitted to neurons. Furthermore, key cell types, such as basal progenitors and neurons, exhibit a highly flexible polarity. We suggest that both inheritance and flexibility of cell polarity are implicated in the amplification of basal progenitors and tangential dispersion of neurons, which are key features of the evolutionary expansion of the neocortex.

Octopuses have evolved incredibly large and complex nervous systems that allow them to perform impressive behaviors, like plan ahead, navigate and solve puzzles. The nervous system of the common octopus (also known as Octopus vulgaris) contains over half a billion nerves cells called neurons, similar to the number found in small primates. Two thirds of these cells reside in the octopuses’ arms, while the rest make-up a central brain that sits between their eyes. Very little is known about how this central brain forms in the embryo, including where the cells originate and which molecular factors drive their maturation in to adult cells. To help answer these questions, Deryckere et al. studied the brain of Octopus vulgaris at different stages of early development using various cell staining and imaging techniques. The experiments identified an important pool of dividing cells which sit in an area outside the central brain called the ‘lateral lips’. In these cells, genes known to play a role in neural development in other animals are active, indicating that the cells had not reached their final, mature state. In contrast, the central brain did not seem to contain any of these immature cells at the point when it was growing the most. To investigate this further, Deryckere et al. used fluorescent markers to track the progeny of the dividing cells during development. This revealed that cells in the lateral lips take on a specific neuronal fate before migrating to their target region in the central brain. Newly matured neurons have also been shown to travel large distances in the embryos of vertebrates, suggesting that this mechanism may be a common strategy for building large, complex brains. Although the nervous system of the common octopus is comparable to mammals, they evolved from a very distant branch of the tree of life; indeed, their last common ancestor was a worm-like animal that lived about 600 million years ago. Studying the brain of the common octopus, as done here, could therefore provide new insights into how complex nervous systems, including our own, evolved over time.

Like other sensory systems, the visual system is topographically organized: Its sensory neurons, the photoreceptors, and their targets maintain point-to-point correspondence in physical space, forming a retinotopic map. The iterative wiring of circuits in the visual system conveniently facilitates the study of its development. Over the past few decades, experiments in Drosophila have shed light on the principles that guide the specification and connectivity of visual system neurons. In this review, we describe the main findings unearthed by the study of the Drosophila visual system and compare them with similar events in mammals. We focus on how temporal and spatial patterning generates diverse cell types, how guidance molecules distribute the axons and dendrites of neurons within the correct target regions, how vertebrates and invertebrates generate their retinotopic map, and the molecules and mechanisms required for neuronal migration. We suggest that basic principles used to wire the fly visual system are broadly applicable to other systems and highlight its importance as a model to study nervous system development.

Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.

Cyclin-dependent kinase 5 (Cdk5) controls neuronal migration in the developing cortex when multipolar newborn neurons transform to become bipolar. However, by which mechanisms Cdk5 controls cell adhesion in migrating neurons are not fully understood. In this study, we examined the functional interaction between Cdk5 and N-cadherin (Ncad) in newborn neurons when they undergo the multipolar to bipolar transition in the intermediate zone (IZ). Detailed expression analysis revealed that both Cdk5 and Ncad were present in GFP-electroporated migrating neurons in the IZ. Misexpression of dominant negative Cdk5 into the embryonic brains stalled neuronal locomotion in the lower IZ in which arrested cells were round or multipolar. When Ncad was co-introduced with Cdk5DN, however, cells continue to migrate into the cortical plate (CP) and migrating neurons acquired typical bipolar morphology with a pia-directed leading process. Similarly, downregulation of CDK5 resulted in lesser aggregation ability, reversed by the expression of Ncad in vitro. Down-regulation of activity or protein level of CDK5 did not alter the total amount of NCAD proteins but lowered its surface expression in cells. Lastly, expression of CDK5 and NCAD overlapped in the IZ of the human fetal cortex, indicating that the role of Cdk5 and Ncad in neuronal migration is evolutionarily conserved.

This study investigated the ability of intra-subventricular zone (SVZ) administration of cerebral dopamine neurotrophic factor (CDNF) on neural progenitor cells (NPCs) attraction from the SVZ toward the 6-hydroxydopamine (6-OHDA)-lesioned striatum and improvement of motor dysfunctions in Parkinsonian rats. Male Wistar rats were assigned to four groups of the sham model (Sham), 6-OHDA-lesioned (OH), 6-OHDA-lesioned plus CDNF vehicle (OH+Vehicle), and 6-OHDA-lesioned plus CDNF (OH+CDNF). The animal model of Parkinson's disease (PD) was induced by unilateral intra-striatal infusion of 6-OHDA. Rats in the treatment groups received an intra-SVZ injection of CDNF or the vehicle of CDNF two weeks after PD model induction and were then subjected to the beam and bar tests on days 7, 14, and 21 after CDNF injection. Bromodeoxyuridine (BrdU) was intraperitoneally injected to label newly generated cells. Migration and proliferation of NPCs were assessed by BrdU/doublecortin (DCX) double immunofluorescence method on days 7, 14, and 21 after CDNF infusion. 6-OHDA in the OH group induced catalepsy and increased elapsed time in the beam test compared to the Sham group. However, administration of CDNF improved the motor performance and increased the number of DCX expressing neuroblasts in the SVZ as compared to the OH and OH+Vehicle groups. CDNF also enhanced cell proliferation and increased the number of migrated BrdU- and DCX-positive cells toward the lesioned striatum in the OH+CDNF group. These results suggest that CDNF enhances the proliferation and migration of neural stem cells (NSCs) toward the lesioned striatum accompanied by improvement of PD-induced motor dysfunctions., EXCLI Journal;Vol. 18 2019

In the developing mammalian cerebral cortex, newly generated neurons migrate toward the pial surface to form a mammalian-specific six-layered cerebral cortex. Genetic studies of human neurological diseases have suggested the involvement of several molecules in cortical neuronal migration. In vivo electroporation is another powerful tool for understanding the molecular mechanisms of neuronal migration. By using these techniques, however, it is difficult to understand molecular basis of time-dependent changes of neuronal morphologies. Here, we introduce a pharmacological approach to cerebral cortical development. Major advantages of the pharmacological approach include the transient suppression of molecules of interest and analyzing time-dependent changes of neuronal morphologies. It also allows us to search molecules regulating neuronal migration with comparative ease. We propose the complementarity between the pharmacological approach and genetics or in vivo electroporation experiments.

Neuronal connectivity in the cortex is determined by the laminar positioning of neurons. An important determinant of laminar positioning is likely to be the control of leading process behavior during migration, maintaining their tips directed toward the pia. In this study, we provide evidence that pial bone morphogenetic protein (Bmp) signaling regulates cortical neuronal migration during cortical layer formation. Specific disruption of pial Bmp ligands impaired the positioning of early-born neurons in the deep layer; further, cell-autonomous inhibition of Smad4, a core nuclear factor mediating Bmp signaling, in the cortical radial glial cells or postmitotic cortical neurons also produced neuronal migration defects that blurred the cortical layers. We found that leading processes were abnormal and that this was accompanied by excess dephosphorylated cofilin-1, an actin-severing protein, in Smad4 mutant neurons. This suggested that regulation of cofilin-1 might transduce Bmp signaling in the migrating neurons. Ectopic expression of a phosphorylation-defective form of cofilin-1 in the late-born wild-type neurons led them to stall in the deep layer, similar to the Smad4 mutant neurons. Expression of a phosphomimetic variant of cofilin-1 in the Smad4 mutant neurons rescued the migration defects. This suggests that cofilin-1 activity underlies Bmp-mediated cortical neuronal migration. This study shows that cofilin-1 mediates pial Bmp signaling during the positioning of cortical neurons and the formation of cortical layers.

The human insula is a key node in a neuronal network which integrates interoceptive stimuli from the own body, and exteroceptive stimuli from the environment, and thus maintains the autonomic, emotional and socio-cognitive homeostasis of the body. In the last years, the insula has come into the focus of attention. Comparative anatomical studies showed that in many species the insula forms the lateral edge of the cortex. Very little is known about the prenatal development of the human insula, which is the first cortical region to mature. The origin of the pyramidal neurons for the insula is a small sector of the proliferating ventricular/subventricular zone at the cortico-striatal boundary (CSB). The CSB contains the radial glia cells, which are stem cells and give rise to a dense fascicle of radial glia processes. This fascicle traverses the external capsule and serves as a migration substrate for the neuroblasts on their way from the CSB into the insula. Around the 10/11th week of gestation, the lateral ventricle and its adjacent structures including the CSB bend in a C-shaped fashion. The insula now develops between a dorsal, fronto-parietal and a ventral, temporal CSB, which provide descending and ascending streams of neuroblasts, respectively, migrating along the radial glia fascicle. As a consequence of the ventricular rotation during ontogenesis, the human insula changes its initial position at the lateral edge of the cortex to its final central location, which reflects its integrative functions in brain activity.

International audience; Reelin, a glycoprotein of the extracellular matrix, has been the focus of several studies over the years, mostly for its role in cell migration. Here we report the role of this molecule and of its downstream pathways in post-mitotic neurons and how they contribute to neural circuit assembly, refinement and function. Accumulating evidence has pointed at a major role for Reelin in axonal guidance, synaptogenesis and dendritic spine formation. In particular new evidence points at a direct role in axonal targeting and refinement at the target site. In addition, recent advances highlight new functions of Reelin in the modulation of synaptic activity, plasticity and behavior and it directly regulates GABA receptors expression and stability. We discuss these findings in the context of neurodevelopmental disorders. Highlights  Reelin signaling is required for axonal targeting and refinement at the target site.  Reelin signaling regulates dendritogenesis and spine formation in mature neurons.  Reelin modulates GABA receptors expression and stability, pre-and-post-synaptically.  Reelin is important for hippocampal integrity, synaptic plasticity and behavior.

The assembly of neuronal circuits during development depends on guidance of axonal growth cones by molecular cues deposited in their environment. While a number of families of axon guidance molecules have been identified and reviewed, important and diverse activities of traditional growth factors are emerging. Besides clear and well recognized roles in the regulation of cell division, differentiation and survival, new research shows later phase roles for a number of growth factors in promoting neuronal migration, axon guidance and synapse formation throughout the nervous system.

Neuronal migration is a fundamental brain development process that allows cells to move from their birthplaces to their sites of integration. Although neuronal migration largely ceases during embryonic and early postnatal development, neuroblasts continue to be produced and to migrate to a few regions of the adult brain such as the dentate gyrus and the subventricular zone (SVZ). In the SVZ, a large number of neuroblasts migrate into the olfactory bulb (OB) along the rostral migratory stream (RMS). Neuroblasts migrate in chains in a tightly organized micro-environment composed of astrocytes that ensheath the chains of neuroblasts and regulate their migration; the blood vessels that are used by neuroblasts as a physical scaffold and a source of molecular factors; and axons that modulate neuronal migration. In addition to diverse sets of extrinsic micro-environmental cues, long-distance neuronal migration involves a number of intrinsic mechanisms, including membrane and cytoskeleton remodeling, Ca2+signaling, mitochondria dynamics, energy consumption, and autophagy. All these mechanisms are required to cope with the different micro-environment signals and maintain cellular homeostasis in order to sustain the proper dynamics of migrating neuroblasts and their faithful arrival in the target regions. Neuroblasts in the postnatal brain not only migrate into the OB but may also deviate from their normal path to migrate to a site of injury induced by a stroke or by certain neurodegenerative disorders. In this review, we will focus on the intrinsic mechanisms that regulate long-distance neuroblast migration in the adult brain and on how these pathways may be modulated to control the recruitment of neuroblasts to damaged/diseased brain areas.

Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.

Hormones are key factors throughout neurodevelopment, and thyroid hormones are essential for a correct maturation of the nervous system. Thyroid hormones’ pleiotropic actions during brain development include the regulation of cell generation and survival, differentiation, migration, growth, and retraction of cellular processes, synaptogenesis, myelination, and establishment of neuronal circuits. Indeed, thyroid hormones act on different progenitor cells, glial cells, and neurons subtypes, at specific regional and temporal patterns. They are key factors involved in the regulation of the expression of target genes, including cell cycle proteins, growth factors, and neurotrophins, cytoskeleton proteins, axon guidance and synaptogenesis-related proteins, myelin proteins, and enzymes related to neurotransmitter metabolism. In the fetus, the maternal thyroid hormone supply is essential for a correct neurodevelopment, until the fetal thyroid gland is functional. Thyroid hormones deficiency during brain development induces mild to devastating impairments on the neurological outcome of the offspring depending on the severity of the deficiency, its duration, and the time window affected.

For neuronal lamination during cerebral morphogenesis, later-born neurons must migrate through already-accumulated neurons. This neuronal migration is biochemically regulated by signaling molecules and mechanically affected by tissue deformation. To understand the neuronal lamination mechanisms, we constructed a continuum model of neuronal migration in a growing deformable tissue. We performed numerical analyses considering the migration promoted by signaling molecules and the tissue growth induced by neuron accumulation. The results suggest that the promoted migration and the space ensured by tissue growth are essential for neuronal lamination. The proposed model can describe the coupling of mechanical and biochemical mechanisms for neuronal lamination.

Interactions between neurons and their environment are crucial for proper termination of neuronal migration during brain development. In this review, we first introduce the migration behavior of cortical excitatory neurons from neurogenesis to migration termination, focusing on morphological and behavioral changes. We then describe possible requirements for environmental elements, including extracellular matrix proteins and Cajal-Retzius cells in the marginal zone, radial glial cells, and neighboring neurons, to ensure proper migration termination of these neurons at their final destinations. The requirements appear to be highly linked to sequential and/or concurrent changes in adhesiveness of migrating neurons and their surroundings, which allow the neurons to reach their final positions, detach from substrates, and establish stable laminar structures.

Subplate neurons (SpNs) are one of the earliest born and matured neurons in the developing cerebral cortex and play an important role in the early development of the neocortex. It has been known that SpNs have an essential role in thalamocortical axon (TCA) pathfinding and the establishment of the first neural circuit from the thalamus towards cortical layer IV. In addition to this function, it has recently been revealed in mouse corticogenesis that SpNs play an important role in the regulation of radial neuronal migration during the mid-embryonic stage. Moreover, accumulating studies throw light on the possible roles of SpNs in adult brain functions and also their involvement in psychiatric or other neurological disorders. As SpNs are unique to mammals, they may have contributed to the evolution of the mammalian neocortex by efficiently organizing cortical formation during the limited embryonic period of corticogenesis. By increasing our knowledge of the functions of SpNs, we will clarify how SpNs act as an organizer of mammalian neocortical formation.

Neocortical neurons will assemble into exquisite circuits that will ultimately drive multiple advanced functions such as higher cognition, voluntary motor behavior, and conscious sensory perception. To achieve this, a fundamental set of intricate events has to occur that will bring glutamatergic excitatory projection neurons (also called pyramidal neurons) and GABAergic inhibitory (also called interneurons) from their birth sites using two coexistent but distinct modes of migration. Neocortical glutamatergic neurons use radial migration, whereas GABAergic neurons use tangential migration. Each of the two migration mechanisms has multiple cellular steps that are regulated by intricate molecular events. This chapter summarizes current state of knowledge in transcriptional and posttranscriptional mechanisms involved in the control of radial and tangential migration of neocortical neurons.

Peroxisomes are ubiquitous subcellular organelles. Peroxisomal disorders may be divided into disorders of peroxisome biogenesis and single-enzyme disorders. Nearly all of these disorders are expressed in the nervous system. The most common disorder of the group is X-linked adrenoleukodystrophy, which may develop in either childhood or adulthood with various neurologic manifestations. In contrast are the severe biogenesis disorders that are multisystem and may affect neuronal migration with resultant developmental abnormalities, seizures, and progressive demyelination. The diagnosis of these disorders results on the understanding of the biochemical abnormalities and they may reliably diagnosed by biochemical measures or DNA analysis.

Neurons generated in the postnatal V-SVZ form chainlike aggregates and migrate rapidly within a glial tube for a long distance toward the olfactory bulb. These morphological features are not observed during the embryonic period, suggesting that the chain formation and glial tube have roles specific to the neuronal migration in the postnatal brain. Neuronal migration in the postnatal brain may be affected by changes in the physiological condition of the brain, such as neuronal activity, development, and aging. Furthermore, recent evidence suggests that neuronal migration also depends on nonneural systems such as immune and vascular systems. Further analyses of the spatiotemporal interactions between migrating neurons and other cell types, and identification of the molecules mediating these interactions will be necessary to understand the regulatory mechanisms of neuronal migration in the postnatal brain. Neuronal migration in the postnatal brain appears to be a remarkable strategy for modifying postnatal brain functions, and not just a delivery system of newborn neurons from the germinal zone to their destination. Further studies aimed at clarifying the adaptive potential of migrating neurons in the postnatal brain are needed to establish novel strategies for endogenous neuronal regeneration.

Most neurons in the central nervous system assemble to circuits and function in a location that is different from their site of origin. Neuronal migration has strong implications in brain development, and the way the migratory patterns evolved brought major consequences on brain evolution. Here, we review the impact that the two main modes neuronal migration had on vertebrate brain diversity and function. First, radial migration enabled a more efficient production of neurons from the limited proliferative sector and promoted the efficient rearrangement of internal circuits. And second, tangential migration influenced brain evolution at several levels, such as diversifying neuronal types, enhancing network computational capabilities, shifting developmental programs on distant regions, and promoting novel wiring scenarios. We review the evolving modes of neuronal migration that sculpted and diversified vertebrate brains and how they substantially increased brain complexity over vertebrate evolution.

Neocortex development during embryonic stages requires the precise control of mRNA metabolism. Human antigen R (HuR) is a well-studied mRNA-binding protein that regulates mRNA metabolism, and it is highly expressed in the neocortex during developmental stages. Deletion of HuR does not impair neural progenitor cell proliferation or differentiation, but it disturbs the laminar structure of the neocortex. We report that HuR is expressed in postmitotic projection neurons during mouse brain development. Specifically, depletion of HuR in these neurons led to a mislocalization of CDP+ neurons in deeper layers of the cortex. Time-lapse microscopy showed that HuR was required for the promotion of cell motility in migrating neurons. PCR array identified profilin 1 (Pfn1) mRNA as a major binding partner of HuR in neurons. HuR positively mediated the stability of Pfn1 mRNA and influenced actin polymerization. Overexpression of Pfn1 successfully rescued the migration defects of HuR-deleted neurons. Our data reveal a post-transcriptional mechanism that maintains actin dynamics during neuronal migration., Summary: Maintaining actin dynamics is crucial for cell motility. Post-transcriptional regulation plays a pivotal role in supporting actin dynamics during neuronal migration.

N-cadherin, a member of the cadherin family, plays an important role in neural development. In addition, N-cadherin has been reported to be crucial in neuronal migration, axonal outgrowth, and axonal path-finding. However, the mechanism underlying the effects of N-cadherin in neuronal migration is not entirely clear. In this study, we investigated the overexpression or knockdown of N-cadherin in the optic tectum during chicken embryo development, and then analyzed the effect of N-cadherin on neuronal migration. The results showed that compared with the control group, in the N-cadherin knockdown group, the neuronal migration of the optic tectum was significantly affected and could not arrive at destination. The stratum griseum central layer of the optic tectum mainly includes multipolar neurons, which could not be formed after the knockdown of N-cadherin, and more neurons form the bipolar or monopolar neurons compared with the control group. Compared with the control group, more cells stayed in the neuroepithelium layer. The axonal length in the optic tectum was significantly (P

Directed control of neuronal migration, facilitating the correct spatial positioning of neurons, is crucial to the development of a functional nervous system. An understanding of neuronal migration and positioning on patterned surfaces in vitro would also be beneficial for investigators seeking to design culture platforms capable of mimicking the complex functional architectures of neuronal tissues for drug development as well as basic biomedical research applications. This study used coplanar self-assembled monolayer patterns of cytophilic, N-1[3-(trimethoxysilyly)propyl] diethylenetriamine (DETA) and cytophobic, tridecafluoro-1,1,2,2-tetrahydrooctyl-1-trichlorosilane (13F) to assess the migratory behavior and physiological characteristics of cultured neurons. Analysis of time-lapse microscopy data revealed a dynamic procedure underlying the controlled migration of neurons, in response to extrinsic geometric and chemical cues, to promote the formation of distinct two-neuron circuits. Immunocytochemical c...

Neuronal circuits, the functional building blocks of the nervous system, assemble during development through a series of dynamic processes including the migration of neurons to their final position, the growth and navigation of axons and their synaptic connection with target cells. While the role of chemical cues in guiding neuronal migration and axonal development has been extensively analysed, the contribution of mechanical inputs, such as forces and stiffness, has received far less attention. In this article, we review the in vitro and more recent in vivo studies supporting the notion that mechanical signals are critical for multiple aspects of neuronal circuit assembly, from the emergence of axons to the formation of functional synapses. By combining live imaging approaches with tools designed to measure and manipulate the mechanical environment of neurons, the emerging field of neuromechanics will add a new paradigm in our understanding of neuronal development and potentially inspire novel regenerative therapies.

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF overexpression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)+ cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the peri-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex., After a stroke, there are endogenous reparative processes in the brain, but they are not sufficient to repair damaged tissue. We demonstrate that MANF is an essential element for regulating migration of neuroprogenitor cells and identified a signaling pathway of STAT3 to mediate MANF’s effects of increasing the regenerative capacity.

The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3ΔTie2-Cre and VgatΔTie2-Cre), we show that partial or complete loss of GABA release from endothelial cells during embryogenesis results in vascular defects and impairs long-distance migration and positioning of cortical interneurons. The downstream effects of perturbed endothelial cell-derived GABA signaling are critical, leading to lasting changes to cortical circuits and persistent behavioral deficits. Furthermore, we illustrate new mechanisms of activation of GABA signaling in forebrain endothelial cells that promotes their migration, angiogenesis and acquisition of blood-brain barrier properties. Our findings uncover and elucidate a novel endothelial GABA signaling pathway in the CNS that is distinct from the classical neuronal GABA signaling pathway and shed new light on the etiology and pathophysiology of neuropsychiatric diseases, such as autism spectrum disorders, epilepsy, anxiety, depression and schizophrenia.