Migration Of Immature Neurons Research Articles

Ca2+]i fluctuation mediated by T-type Ca2+ channel is required for the differentiation of cortical neural progenitor cells

The fluctuation of intracellular calcium concentration ([Ca2+]i) is known to be involved in various processes in the development of central nervous system, such as the proliferation of neural progenitor cells (NPCs), migration of intermediate progenitor cells (IPCs) from the ventricular zone (VZ) to the subventricular zone (SVZ), and migration of immature neurons from the SVZ to cortical plate. However, the roles of [Ca2+]i fluctuation in NPC development, especially in the differentiation of the self-renewing NPCs into neuron-generating NPCs and immature neurons have not been elucidated. Using calcium imaging of acute cortical slices and cells isolated from mouse embryonic cortex, we examined temporal changes in the pattern of [Ca2+]i fluctuations in VZ cells from E12 to E16. We observed intracellular Ca2+ levels in Pax6-positive self-renewing NPCs decreased with their neural differentiation. In E11, Pax6-positive NPCs and Tuj1-positive immature neurons exhibited characteristic [Ca2+]i fluctuations; few Pax6-positive NPCs exhibited [Ca2+]i transient, but many Tuj1-positive immature neurons did, suggesting that the change in pattern of [Ca2+]i fluctuation correlate to their differentiation. The [Ca2+]i fluctuation during NPCs development was mostly mediated by the T-type calcium channel and blockage of T-type calcium channel in neurosphere cultures increased the number of spheres and inhibited neuronal differentiation. Consistent with this finding, knockdown of Cav3.1 by RNAi in vivo maintained Pax6-positive cells as self-renewing NPCs, and simultaneously suppressing their neuronal differentiation of NPCs into Tbr1-positive immature neurons. These results reveal that [Ca2+]i fluctuation mediated by Cav3.1 is required for the neural differentiation of Pax6-positive self-renewing NPCs.

An implantable human stem cell-derived tissue-engineered rostral migratory stream for directed neuronal replacement

The rostral migratory stream (RMS) facilitates neuroblast migration from the subventricular zone to the olfactory bulb throughout adulthood. Brain lesions attract neuroblast migration out of the RMS, but resultant regeneration is insufficient. Increasing neuroblast migration into lesions has improved recovery in rodent studies. We previously developed techniques for fabricating an astrocyte-based Tissue-Engineered RMS (TE-RMS) intended to redirect endogenous neuroblasts into distal brain lesions for sustained neuronal replacement. Here, we demonstrate that astrocyte-like-cells can be derived from adult human gingiva mesenchymal stem cells and used for TE-RMS fabrication. We report that key proteins enriched in the RMS are enriched in TE-RMSs. Furthermore, the human TE-RMS facilitates directed migration of immature neurons in vitro. Finally, human TE-RMSs implanted in athymic rat brains redirect migration of neuroblasts out of the endogenous RMS. By emulating the brain’s most efficient means for directing neuroblast migration, the TE-RMS offers a promising new approach to neuroregenerative medicine.

Life and Death of Immature Neurons in the Juvenile and Adult Primate Amygdala.

In recent years, a large population of immature neurons has been documented in the paralaminar nucleus of the primate amygdala. A substantial fraction of these immature neurons differentiate into mature neurons during postnatal development or following selective lesion of the hippocampus. Notwithstanding a growing number of studies on the origin and fate of these immature neurons, fundamental questions about the life and death of these neurons remain. Here, we briefly summarize what is currently known about the immature neurons present in the primate ventral amygdala during development and in adulthood, as well as following selective hippocampal lesions. We provide evidence confirming that the distribution of immature neurons extends to the anterior portions of the entorhinal cortex and layer II of the perirhinal cortex. We also provide novel arguments derived from stereological estimates of the number of mature and immature neurons, which support the view that the migration of immature neurons from the lateral ventricle accompanies neuronal maturation in the primate amygdala at all ages. Finally, we propose and discuss the hypothesis that increased migration and maturation of neurons in the amygdala following hippocampal dysfunction may be linked to behavioral alterations associated with certain neurodevelopmental disorders.

Histogenetic Radial Models as Aids to Understanding Complex Brain Structures: The Amygdalar Radial Model as a Recent Example.

The radial dimension expands during central nervous system development after the proliferative neuroepithelium is molecularly patterned. The process is associated with neurogenesis, radial glia scaffolding, and migration of immature neurons into the developing mantle stratum. Radial histogenetic units, defined as a delimited neural polyclone whose cells share the same molecular profile, are molded during these processes, and usually become roughly stratified into periventricular, intermediate, and superficial (subpial) strata wherein neuronal cell types may differ and be distributed in various patterns. Cell-cell adhesion or repulsion phenomena together with interaction with local intercellular matrix cues regulate the acquisition of nuclear, reticular, or layer histogenetic forms in such strata. Finally, the progressive addition of inputs and outputs soon follows the purely neurogenetic and radial migratory phase. Frequently there is heterochrony in the radial development of adjacent histogenetic units, apart of peculiarities in differentiation due to non-shared aspects of the respective molecular profiles. Tangential migrations may add complexity to radial unit cytoarchitecture and function. The study of the contributions of such genetically controlled radial histogenetic units to the emerging complex neural structure is a key instrument to understand central nervous system morphology and function. One recent example in this scenario is the recently proposed radial model of the mouse pallial amygdala. This is theoretically valid generally in mammals (Garcia-Calero et al., 2020), and subdivides the nuclear complex of the pallial amygdala into five main radial units. The approach applies a novel ad hoc amygdalar section plane, given the observed obliquity of the amygdalar radial glial framework. The general relevance of radial unit studies for clarifying structural analysis of all complex brain regions such as the pallial amygdala is discussed, with additional examples.

Altered Hippocampal Neurogenesis during the First 7 Days after a Fluid Percussion Traumatic Brain Injury

Traumatic brain injury (TBI) is a devastating disorder causing negative outcomes in millions of people each year. Despite the alarming number of brain injuries and the long-term detrimental outcomes that can be associated with TBI, treatment options are lacking. Extensive investigation is underway, in hopes of identifying effective treatment strategies. Among the most state-of-the-art strategies is cell replacement therapy. TBI is a seemingly good candidate for cell replacement studies because there is often loss of neurons. However, translation of this therapy has not yet been successful. It is possible that a better understanding of endogenous neurogenic mechanisms after TBI could lead to more efficacious study designs using exogenous cell replacement strategies. Therefore, this study was designed to examine the number and migration of immature neurons at 1 and 7 d after a fluid percussion TBI. The results show that the number of immature neurons increases from 7 d after a fluid percussion injury (FPI), and there is ectopic migration of doublecortin (DCX+) immature neurons into the hilar region of the dentate gyrus. These results add important data to the current understanding of the endogenous neurogenic niche after TBI. Follow-up studies are needed to better understand the functional significance of elevated neurogenesis and aberrant migration into the hilus.

RP58 Regulates the Multipolar-Bipolar Transition of Newborn Neurons in the Developing Cerebral Cortex

Accumulating evidence suggests that many brain diseases are associated with defects in neuronal migration, suggesting that this step of neurogenesis is critical for brain organization. However, the molecular mechanisms underlying neuronal migration remain largely unknown. Here, we identified the zinc-finger transcriptional repressor RP58 as a key regulator of neuronal migration via multipolar-to-bipolar transition. RP58(-/-) neurons exhibited severe defects in the formation of leading processes and never shifted to the locomotion mode. Cre-mediated deletion of RP58 using in utero electroporation in RP58(flox/flox) mice revealed that RP58 functions in cell-autonomous multipolar-to-bipolar transition, independent of cell-cycle exit. Finally, we found that RP58 represses Ngn2 transcription to regulate the Ngn2-Rnd2 pathway; Ngn2 knockdown rescued migration defects of the RP58(-/-) neurons. Our findings highlight the critical role of RP58 in multipolar-to-bipolar transition via suppression of the Ngn2-Rnd2 pathway in the developing cerebral cortex.

Current problems of in vivo developmental neurotoxicity tests and a new in vivo approach focusing on each step of the developing central nervous system

Developmental neurotoxicity (DNT) tests usually focus on postnatal indicators, such as behavior and neuropathology, for the detection of chemically induced neurodevelopmental defects in the central nervous system (CNS). However, low reliability, especially low reproducibility, of behavioral results often causes concern among scientists and the scientific community in general. Guidance of neurohistopathological examination in the DNT guideline also has some shortcomings, especially relating to the methodological aspects. Ongoing international trends in DNT tests have shifted from the use of original in vivo animal (mammalian) studies to in vitro experiments using cell cultures and/or non-mammalian species, such as fish. In vitro systems might initially be useful to screen test chemicals for their DNT potential. Although in vitro systems are employed as alternative approaches for DNT studies, the use of in vivo studies based on animal models remains an important factor when data are to be extrapolated to the human case. In this review, a new in vivo approach that focuses on histopathological observation of each developmental step of the CNS, such as proliferation of neural stem cells, migration of immature neurons, and formation of neural networks, using fetal and neonatal brains after chemical exposure is introduced, and some queries and arguments for current DNT experimental guidelines are discussed.

Expression of hepatocyte growth factor in the serum and cerebrospinal fluid of patients with Parkinson’s disease

Hepatocyte growth factor (HGF), also known as scatter factor, promotes the survival and migration of immature neurons. The HGF receptor c-Met is expressed in neurons. HGF plays an important role as a neurotrophic factor in the brain. HGF is produced by a wide variety of cells and is found in many physiological fluids, including serum and cerebrospinal fluid (CSF). Since CSF is in contact with the extracellular space of the brain, biochemical brain modifications are, to some extent, reflected in the CSF, and peptide and growth factors in the CSF can be used as biomarkers of disease. In this study, CSF and serum HGF concentrations were measured in patients with Parkinson’s disease. The study population comprised 33 patients with Parkinson’s disease and 38 normal controls. Western blot analysis using an anti-HGF antibody confirmed the presence of HGF in serum and CSF. No significant changes in serum HGF were observed in this study. However, CSF HGF expression was higher in patients with Parkinson’s disease than in controls ( p < 0.001). This finding indicates that HGF may be involved in the pathophysiology of Parkinson’s disease.

Poststroke Neurogenesis: Emerging Principles of Migration and Localization of Immature Neurons

Stroke induces proliferation of newly born neurons in the subventricular zone, migration of these immature neurons away from the SVZ, and localization within peri-infarct tissues. These 3 processes of proliferation, migration, and localization constitute distinct spatial and temporal zones within poststroke neurogenesis with distinct molecular and cell-cell signaling environments. Immature neurons migrate after stroke in close association with blood vessels and astrocytic processes, in a process that involves matrix metalloproteinases. This poststroke migration shares similar features with normal neuroblast migration in the rostral migratory stream. Immature neurons localize in the peri-infarct cortex in a neurovascular niche where neurogenesis is causally linked to angiogenesis through the vascular factors SDF-1 and angiopoietin-1. Other vascular and neuronal growth factors have also been linked to poststroke neuroblast localization in peri-infarct tissue, including erythropoietin. Most data on poststroke neurogenesis derive from laboratory rodents, which may have an abnormal or blunted degree of neurogenesis and neuroplasticity compared to normal, wild rodents. This will likely affect translational application of the principles of poststroke neurogenesis from mouse to man. NEUROSCIENTIST 14(4):369–380, 2008. DOI: 10.1177/1073858407309545

Cerebellar cortical-layer-specific control of neuronal migration by pituitary adenylate cyclase-activating polypeptide

Migration of immature neurons is essential for forming the cortical layers and nuclei. Impairment of migration results in aberrant neuronal cytoarchitecture, which leads to various neurological disorders. Neurons alter the mode, tempo and rate of migration when they translocate through different cortical layers, but little is known about the mechanisms underlying this process. Here we show that endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) has short-term and cortical-layer-specific effects on granule cell migration in the early postnatal mouse cerebellum. Application of exogenous PACAP significantly slowed the migration of isolated granule cells and shortened the leading process in the microexplant cultures of the postnatal day (P)0-3 cerebella. Interestingly, in the cerebellar slices of P10 mice, application of exogenous PACAP significantly inhibited granule cell migration in the external granular layer (EGL) and molecular layer (ML), but failed to alter the movement in the Purkinje cell layer (PCL) and internal granular layer (IGL). In contrast, application of PACAP antagonist accelerated granule cell migration in the PCL, but did not change the movement in the EGL, ML and IGL. Inhibition of the cAMP signaling and the activity of phospholipase C significantly reduced the effects of exogenous PACAP on granule cell migration. The PACAP action on granule cell migration was transient, and lasted for approximately 2 h. The duration of PACAP action on granule cell migration was determined by the desensitization of its receptors and prolonged by inhibiting the protein kinase C. Endogenous PACAP was present sporadically in the bottom of the ML, intensively in the PCL, and throughout the IGL. Collectively, these results indicated that PACAP acts on granule cell migration as “a brake (stop signal) for cell movement.” Furthermore, these results suggest that endogenous PACAP slows granule cell migration when the cells enter the PACAP-rich PCL, and 2 h later the desensitization of PACAP receptors allows the cells to accelerate the rate of migration and to actively move within the PACAP-rich IGL. Therefore, endogenous PACAP may provide a cue that regulates granule cell migration in a cerebellar cortical-layer-specific manner.

A role for ion channels in glioma cell invasion

Many cells, including neuronal and glial progenitor cells, stem cells and microglial cells, have the capacity to move through the extracellular spaces of the developing and mature brain. This is particularly pronounced in astrocyte-derived tumors, gliomas, which diffusely infiltrate the normal brain. Although a significant body of literature exists regarding signals that are involved in the guidance of cells and their processes, little attention has been paid to cell-shape and cell-volume changes of migratory cells. However, extracellular spaces in the brain are very narrow and represent a major obstacle that requires cells to dynamically regulate their volume. Recent studies in glioma cells show that this involves the secretion of Cl− and K+ with water. Pharmacological inhibition of Cl− channels impairs their ability to migrate and limits tumor progression in experimental tumor models. One Cl−-channel inhibitor, chlorotoxin, is currently in Phase II clinical trials to treat malignant glioma. This article reviews our current knowledge of cell-volume changes and the role of ion channels during the migration of glioma cells. It also discusses evidence that supports the importance of channel-mediated cell-volume changes in the migration of immature neurons and progenitor cells during development. New unpublished data is presented, which demonstrates that Cl− and K+ channels involved in cell shrinkage localize to lipid-raft domains on the invadipodia of glioma cells and that their presence might be regulated by trafficking of these proteins in and out of lipid rafts.

Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus

Hepatocyte growth factor (HGF) promotes the survival and migration of immature neurons, but its role in the mature brain has remained elusive. In the hippocampus of juvenile rats, we found that the HGF receptor c-Met was expressed in neurons. Furthermore, it was highly Tyr-phosphorylated, more so than in the liver under normal conditions, suggesting that the receptor is activated and that HGF may act continuously in the intact brain. Exogenously applied HGF enhanced synaptic long-term potentiation (LTP) in the CA1 region of hippocampus, but did not affect long-term depression. We further found that HGF augmented N-methyl-D-aspartate receptor-mediated currents in both slices and dissociated neurons. This augmentation is likely to underlie the enhancement of LTP. Considering that the expression of both HGF and c-Met are known to be induced by ischemic stimuli, this modulation would provide a novel understanding of a neuronal regulatory systems shared with pathogenic ischemic states.

Chemokine receptors: signposts to brain development and disease.

During the development of the nervous system, populations of progenitor cells that eventually become neurons and glia face the complex task of finding their way from their place of birth to their final destinations. What are the molecular processes that provide the information for guiding progenitor cells along their way? In this article, we discuss recent information indicating that chemokines and their receptors are of great importance in directing the proliferation and migration of immature neurons, glia and their precursors. Furthermore, chemokine receptor function in the nervous system continues to be important throughout adult life, and chemokines participate in various brain disorders, including AIDS dementia, neuroinflammatory disease and neuroplasia, making them important potential therapeutic targets in these cases.

Localization of platelet-activating factor receptor in the rat brain.

Platelet-activating factor (PAF) has diverse effects on various cells and tissues despite its initial characterization as an activator of platelets (Braquet et al., 1987; Izumi and Shimizu, 1995). PAF is involved in a wide variety of events in the central nervous system (CNS). This factor is related to post-ischemic neuronal injury (Panetta et al., 1989), human immuno-deficiency virus (HIV)-associated neuronal cell death (Gelbard et al., 1994), alteration of synaptic transmission (Clark et al., 1992), and induction of long-term potentiation (LTP) (Wieraszko et al., 1993; Kato et al., 1994). Also, the roles of PAF in CNS development have lately attracted attention, since a subunit of PAF acetylhydrolase is the product of the causative gene for Miller-Dieker lissencephaly (Hattori et al., 1994), a disorder due to incomplete migration of immature neurons to the cerebral cortex.

Mode of neuronal migration of the pontine stream in fetal mice

The migration of immature neurons in the pontomedullary subpial region was examined in fetal mice by light and electron microscopy. Immature pontine cells were observed forming a cell strand from the ventral aspect of the fourth ventricle to the pontine flexure during the period between the 14th and 17th day of gestation. These cells were elongated and oriented parallel to the direction of migration, and displayed features of immature neurons: they contained a high concentration of ribosomal rosettes and a few cisternae of rough endoplasmic reticula, as well as Golgi apparatus, mitochondria, microtubules and centrioles. Many of the neurons extended leading processes, and these contained longitudinally-arrayed microtubules. Filopodia extending from the processes were found beneath the pia mater. Relocating cells displayed contact relationships between themselves; in the caudal part of the stream, translocating neurons were apposed to each other and fibers of various diameters, and in the rostral area of the stream, many fibers were noted, and corresponded to leading processes of relocating neurons, to which other cell bodies had close contact. From the arrangement of the immature neurons and their processes, it can be inferred that developing fibers act as guidance substrates for the translocation of embryonic pontine neurons.

Migration of immature neurons along tangentially oriented fibers in the subpial part of the fetal mouse medulla oblongata.

Migration of neuronal cells in the subpial part of the medulla oblongata was examined in the fetal mouse by light and electron microscopy. Cells were observed forming a migratory stream in the period between the thirteenth and sixteenth days of gestation, and were associated with tangentially oriented fibers. Many of these tangential fibers were present prior to the onset of the migration, and the fibers were filled with longitudinally arrayed microtubules. The cell-bodies were elongated and arranged along, and often apposed to the fibers. Some relocating neurons extended fibers, i.e. leading processes, in the direction of the migration. Generally, these cells exhibited features of immature neurons; they displayed a high concentration of ribosomal rosettes and contained mitochondria, Golgi apparatus, a few rough endoplasmic reticula, and occasionally, centrioles. Junctional complexes, coated pits and coated vesicles were frequently observed in the region of the migratory stream, and these structures are considered to be related to cell locomotion. The present findings strongly suggest that such tangential fibers, including leading processes of moving neurons, serve as guidance substrates for the relocation of immature neurons in the mouse subpial medullary region.

Migration of immature neurons in the subpial portion of the fetal mouse medulla oblongata

Migration of immature neurons in the subpial portion of the fetal mouse medulla oblongata