How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex (original) (raw)
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How neurons migrate: a dynamic in-silico model of neuron migration in the developing cortex
Background Neuronal migration, the process by which neurons migrate from their place of origin to their final position in the brain, is a central process for normal brain development and function. Advances in experimental techniques have revealed much about many of the molecular components involved in this process. Notwithstanding these advances, how the molecular machinery works together to govern the migration process has yet to be fully understood. Here we present a computational model of neuronal migration, in which four key molecular entities, Lis1, DCX, Reelin and GABA, form a molecular program that mediates the migration process. Results The model simulated the dynamic migration process, consistent with in-vivo observations of morphological, cellular and population-level phenomena. Specifically, the model reproduced migration phases, cellular dynamics and population distributions that concur with experimental observations in normal neuronal development. We tested the model under reduced activity of Lis1 and DCX and found an aberrant development similar to observations in Lis1 and DCX silencing expression experiments. Analysis of the model gave rise to unforeseen insights that could guide future experimental study. Specifically: (1) the model revealed the possibility that under conditions of Lis1 reduced expression, neurons experience an oscillatory neuron-glial association prior to the multipolar stage; and (2) we hypothesized that observed morphology variations in rats and mice may be explained by a single difference in the way that Lis1 and DCX stimulate bipolar motility. From this we make the following predictions: (1) under reduced Lis1 and enhanced DCX expression, we predict a reduced bipolar migration in rats, and (2) under enhanced DCX expression in mice we predict a normal or a higher bipolar migration. Conclusions We present here a system-wide computational model of neuronal migration that integrates theory and data within a precise, testable framework. Our model accounts for a range of observable behaviors and affords a computational framework to study aspects of neuronal migration as a complex process that is driven by a relatively simple molecular program. Analysis of the model generated new hypotheses and yet unobserved phenomena that may guide future experimental studies. This paper thus reports a first step toward a comprehensive in-silico model of neuronal migration.
Molecular control of neuronal migration
Bioessays, 2002
Our understanding of neuronal migration has been advanced by multidisciplinary approaches. At the cellular level, tangential and radial modes of neuronal migration contribute to different populations of neurons and have differential dependence on glial cells. At the molecular level, extracellular guidance cues have been identified and intracellular signal transduction pathways are beginning to be revealed. Interestingly, mechanisms guiding axon projection and neuronal migration appear to be conserved with those for chemotactic leukocytes. BioEssays 24:821–827, 2002. © 2002 Wiley Periodicals, Inc.
Modes and Mishaps of Neuronal Migration in the Mammalian Brain
Journal of Neuroscience, 2008
The ability of neurons to migrate to their appropriate positions in the developing brain is critical to brain architecture and function. Recent research has elucidated different modes of neuronal migration and the involvement of a host of signaling factors in orchestrating the migration, as well as vulnerabilities of this process to environmental and genetic factors. Here we discuss the role of cytoskeleton, motor proteins, and mechanisms of nuclear translocation in radial and tangential migration of neurons. We will also discuss how these and other events essential for normal migration of neurons can be disrupted by genetic and environmental factors that contribute to neurological disease in humans.
Journal of Neuroscience, 2010
Heterozygous LIS1 mutations and males with loss of the X-linked DCX result in lissencephaly, a neuronal migration defect. LIS1 regulates nuclear translocation and mitotic division of neural progenitor cells, while the role of DCX in cortical development remains poorly understood. Here, we uncovered novel neuronal migration and proliferation defects in the Dcx mutant embryonic brains. Although cortical organization was fairly well preserved, Dcx(ko/Y) neurons displayed defective migration velocities similar to Lis1(+/ko) neurons when characterized by time-lapse video-microscopy of embryonic cortical slices. Dcx(ko/Y) migrating neurons displayed novel multidirectional movements with abnormal morphology and increased branching. Surprisingly, Dcx(ko/Y) radial glial cells displayed spindle orientation abnormalities similar to Lis1(+/ko) cells that in turn lead to moderate proliferation defects both in vivo and in vitro. We found functional genetic interaction of the two genes, with the combined effects of Lis1 haploinsufficiency and Dcx knock-out leading to more severe neuronal migration and proliferation phenotypes in the Lis1(+/ko);Dcx(ko/Y) male double mutant compared with the single mutants, resulting in cortical disorganization and depletion of the progenitor pool. Thus, we provide definitive evidence for a critical role for Dcx in neuronal migration and neurogenesis, as well as for the in vivo genetic interaction of the two genes most commonly involved in human neuronal migration defects.
Neuronal migration mechanisms in development and disease
Current Opinion in Neurobiology, 2010
Neuronal migration is a fundamental process that determines the final allocation of neurons in the nervous system, establishing the basis for the subsequent wiring of neural circuitry. From cell polarization to target identification, neuronal migration integrates multiple cellular and molecular events that enable neuronal precursors to move across the brain to reach their final destination. In this review we summarize novel findings on the key processes that govern the cell biology of migrating neurons, describing recent advances in their molecular regulation in different migratory pathways of the brain, spinal cord, and peripheral nervous system. We will also review how this basic knowledge is contributing to a better understanding of the etiology and pathophysiology of multiple neurological syndromes in which neuronal migration is disrupted.
Direct Evidence for Homotypic, Glia-Independent Neuronal Migration
Neuron, 1997
migration occurs in the anterior forebrain of neonatal Valencia University and adult rodents (Luskin, 1993; Lois and Alvarez-Buylla, Spain 1994). Neuronal precursors born in the subventricular zone (SVZ) of lateral ventricles migrate 3-8 mm tangentially through the SVZ (Doetsch and Alvarez-Buylla, Summary 1996) and along its anterior extension, called the rostral migratory stream (RMS), to reach the olfactory bulb Neuronal precursors born in the subventricular zone where they differentiate into granule and periglomerular (SVZ) of the neonatal and adult rodent brain migrate neurons.
Cell-autonomous and cell-to-cell signalling events in normal and altered neuronal migration
European Journal of Neuroscience, 2011
The cerebral cortex is a complex six-layered structure that contains an important diversity of neurons, and has rich local and extrinsic connectivity. Among the mechanisms governing the cerebral cortex construction, neuronal migration is perhaps the most crucial as it ensures the timely formation of specific and selective neuronal circuits. Here, we review the main extrinsic and extrinsic factors involved in regulating neuronal migration in the cortex and describe some environmental factors interfering with their actions.
Auto-attraction of neural precursors and their neuronal progeny impairs neuronal migration
Nature Neuroscience, 2013
nature neuroscience advance online publication B r i e f c o m m u n i c at i o n s Transplantation of neural stem or progenitor cells is an interesting prospect for neuronal replacement in various neurological disorders 1-3 . The efficacy of such transplants will critically depend on efficient migration and integration of donor neurons into the host brain. Neural transplants placed into the adult brain generally form dense clusters at the site of implantation, with only restricted migration of graft-derived neurons into the host brain 4-6 . It has been suggested that migration of transplanted cells might be hampered because the tissue is already fully established, guiding cues are limited and the space is more constricted 7 . In addition, glial scarring at the site of engraftment has been considered to inhibit neuronal migration . We hypothesized that graft-intrinsic interactions between NPCs and their neuronal progeny might interfere with neuronal migration.
Frontiers in Cell and Developmental Biology, 2019
Central nervous system neurons become postmitotic when radial glia cells divide to form neuroblasts. Neuroblasts may migrate away from the ventricle radially along glia fibers, in various directions or even across the midline. We present four cases of unusual migration that are variably connected to either pathology or formation of new populations of neurons with new connectivities. One of the best-known cases of radial migration involves granule cells that migrate from the external granule cell layer along radial Bergman glia fibers to become mature internal granule cells. In various medulloblastoma cases this migration does not occur and transforms the external granule cell layer into a rapidly growing tumor. Among the ocular motor neurons is one unique population that undergoes a contralateral migration and uniquely innervates the superior rectus and levator palpebrae muscles. In humans, a mutation of a single gene ubiquitously expressed in all cells, induces innervation defects only in this unique motor neuron population, leading to inability to elevate eyes or upper eyelids. One of the bestknown cases for longitudinal migration is the facial branchial motor (FBM) neurons and the overlapping inner ear efferent population. We describe here molecular cues that are needed for the caudal migration of FBM to segregate these motor neurons from the differently migrating inner ear efferent population. Finally, we describe unusual migration of inner ear spiral ganglion neurons that result in aberrant connections with disruption of frequency presentation. Combined, these data identify unique migratory properties of various neuronal populations that allow them to adopt new connections but also sets them up for unique pathologies.
Cell migration promotes dynamic cellular interactions to control cerebral cortex morphogenesis
Nature Reviews Neuroscience, 2019
Cell migration controls key morphogenic events that shape the nervous system, ranging from neural tube closure to brain formation. During cerebral cortex development, cell migration is essential to set a precise temporal and spatial distribution pattern of neural cells that further engage in dynamic crosstalk to coordinate their maturation. Cerebral cortical activity relies on neural circuits formed of two main classes of neurons: excitatory projection neurons (PNs) that migrate along radial glia (RG) fibres within the cortex and inhibitory interneurons (INs) that originate from the ventral forebrain and reach the cortex along two stereotypical tangential routes 1. These neuronal classes include multiple subtypes for which proper laminar positioning and balanced integration into neural networks are determinant factors for cortical function. Cortical cytoarchitectonics reflects interplays between cell extrinsic cues and intrinsic mechanisms that coordinate the migration of neurons from their birthplace to a final destination, where they assemble into functional circuits. Most of these signals are involved in the control of cytoskeletal elements and their regulators to support dynamic shape changes underlying cell motility and allocation to ad hoc cortical layers 2. Migrating neurons not only receive important cues that direct their navigation and differentiation into the cortex but also influence morphogenetic events occurring in the vicinity of their migratory path. Recent reports have placed glia, and in particular microglia, the resident macrophage of the brain, as essential players for cortical morphogenesis via regulation of brain wiring and IN migration in the cortical wall. However, despite their prominent roles in cortical development, the migration pattern of the glial cells that transiently or permanently populate the cerebral cortex remains largely unexplored 3,4 Here, we review the migration strategies adopted by neural cells to navigate in the cortical wall and offer perspectives for the roles of cell migration in the formation of the cerebral cortex. We also discuss how bringing together quantitative experimental analyses with mathematical modelling fosters the discovery of new mechanisms of cortical morphogenesis 5. Furthermore, this Review sheds light on recent technological developments that advance our understanding of human cerebral cortical morphogenesis and help us decipher how cell migration deficits can interfere with this process in brain pathology. Cell migration in cortical development Cell migration is an important process that allows distinct cell types generated in different brain regions to settle in the cerebral cortex during embryogenesis. In mice, transient cell populations start colonizing the dorsal forebrain at embryonic day 10.5 (E10.5), and these cells guide the later migration and placement in the developing cortex of neurons generated between E11.5 and E18.5. In addition, most glial cells invade the cortical wall concurrently with neurons (Fig. 1a), with which some establish crosstalk. Cell migration strategies Discontinuous migration of cortical interneurons. Cortical INs (cINs) exist in different shapes and forms, and their progenitors initiate interneuron specification in the ganglionic eminences (GEs) at the onset of corticogenesis and before engaging in tangential migration 6,7. Transcriptional programmes are largely conserved Cytoarchitectonics The cellular composition of a biological tissue. Cortical wall Part of the dorsal forebrain that corresponds to the presumptive cerebral cortex. Interneuron specification Cellular process engaging a precursor to self-autonomously acquire functional and morphological features of interneurons when placed in a neutral environment.