Neuritin 1 promotes neuronal migration (original) (raw)
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Mouse neuron navigator 1, a novel microtubule-associated protein involved in neuronal migration
2005
The development of the nervous system (NS) requires the coordinated migration of multiple waves of neurons and subsequent processes of neurite maturation, both involving selective guidance mechanisms. In Caenorhabditis elegans, unc-53 codes for a new multidomain protein involved in the directional migration of a subset of cells. We describe here the first functional characterization of the mouse homologue, mouse Neuron navigator 1 (mNAV1), whose expression is largely restricted to the NS during development. EGFP-mNAV1 associates with microtubules (MTs) plus ends present in the growth cone through a new microtubule-binding (MTB) domain. Moreover, its overexpression in transfected cells leads to MT bundling. The abolition of mNAV1 causes loss of directionality in the leading processes of pontinemigrating cells, providing evidence for a role of mNAV1 in mediating Netrin-1-induced directional migration.
Doublecortin is a Microtubule-Associated Protein and is Expressed Widely by Migrating Neurons
Neuron, 1999
Center structures in neurons and appear to have adopted novel Harvard Institutes of Medicine regulatory mechanisms to solve the unusual morpholog- † Department of Neurology ical challenges that neurons face. In developing neu-Children's Hospital rons, unique anatomic structures include the specialized ‡ Department of Medicine filamentous interstitial junction along the interface of Brigham and Women's Hospital migrating neurons and glial fibers (Gregory et al., 1988), Boston, Massachusetts 02115 the specific orientation of microtubules in the growing axon (Baas et al., 1988), and specialized desmosomes (punctae adherentia) along the length of the leading pro-Summary cess (Gregory et al., 1988). Furthermore, several cytoskeletal proteins are neuron specific (reviewed by Sul-Doublecortin (DCX) is required for normal migration livan, 1988; Julien and Mushynski, 1998), and even the of neurons into the cerebral cortex, since mutations in common cytoskeletal proteins appear to have unique the human gene cause a disruption of cortical neuronal ultrastructural localization (Baas and Joshi, 1992) and migration. To date, little is known about the distribuproperties in neurons (Morris and Lasek, 1982; Black et tion of DCX protein or its function. Here, we demonal., 1984), suggesting that novel molecular signals may strate that DCX is expressed in migrating neurons guide these cytoskeletal alterations. throughout the central and peripheral nervous system The identification of genes from human diseases and during embryonic and postnatal development. DCX mouse mutants with defects in neuronal migration may protein localization overlaps with microtubules in culshed light on the pathways regulating these cytoskeletal tured primary cortical neurons, and this overlapping alterations. Within the last few years, the genes for sevexpression is disrupted by microtubule depolymerizaeral human disorders of neuronal migration have been tion. DCX coassembles with brain microtubules, and identified, including Miller-Dieker lissencephaly (LIS1) recombinant DCX stimulates the polymerization of pu-(Reiner et al., 1993) and X-linked lissencephaly/double rified tubulin. Finally, overexpression of DCX in hetercortex syndrome (des Portes et al., 1998; Gleeson et al., ologous cells leads to a dramatic microtubule pheno-1998). X-linked lissencephaly and double cortex syntype that is resistant to depolymerization. Therefore, drome are distinguishable X-linked allelic disorders due DCX likely directs neuronal migration by regulating to a defect in the novel gene doublecortin (gene, DCX; the organization and stability of microtubules. protein, DCX). In X-linked lissencephaly, seen in males with DCX mutations, cortical neuronal migration is se-Introduction verely disrupted, leading to a rudimentary four-layered cortex (Berg et al., 1998). Mutations in DCX in heterozy-Migrating neurons display complex morphological changes gous females lead to a less severe disease, double corduring their migration. Time-lapse imaging of migrattex, in which some neurons form a relatively normal ing neurons (Edmondson and Hatten, 1987; Liesi, 1992; cortex, while a second population of neurons apparently O'Rourke et al., 1992) demonstrates that migration can
Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. The two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial versus tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT-severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex.
Developmental Cell, 2012
The migration of cortical interneurons is characterized by extensive morphological changes that result from successive cycles of nucleokinesis and neurite branching. Their molecular bases remain elusive, and the present work describes how p27 Kip1 controls cell-cycle-unrelated signaling pathways to regulate these morphological remodelings. Live imaging reveals that interneurons lacking p27 Kip1 show delayed tangential migration resulting from defects in both nucleokinesis and dynamic branching of the leading process. At the molecular level, p27 Kip1 is a microtubule-associated protein that promotes polymerization of microtubules in extending neurites, thereby contributing to tangential migration. Furthermore, we show that p27 Kip1 controls actomyosin contractions that drive both forward translocation of the nucleus and growth cone splitting. Thus, p27 Kip1 cell-autonomously controls nucleokinesis and neurite branching by regulating both actin and microtubule cytoskeletons.
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.
Guiding neuronal cell migrations
Cold Spring Harbor perspectives in biology, 2010
Neuronal migration is, along with axon guidance, one of the fundamental mechanisms underlying the wiring of the brain. As other organs, the nervous system has acquired the ability to grow both in size and complexity by using migration as a strategy to position cell types from different origins into specific coordinates, allowing for the generation of brain circuitries. Guidance of migrating neurons shares many features with axon guidance, from the use of substrates to the specific cues regulating chemotaxis. There are, however, important differences in the cell biology of these two processes. The most evident case is nucleokinesis, which is an essential component of migration that needs to be integrated within the guidance of the cell. Perhaps more surprisingly, the cellular mechanisms underlying the response of the leading process of migrating cells to guidance cues might be different to those involved in growth cone steering, at least for some neuronal populations.
Proceedings of the National Academy of Sciences of the United States of America, 2016
Neurons migrate a long radial distance by a process known as locomotion in the developing mammalian neocortex. During locomotion, immature neurons undergo saltatory movement along radial glia fibers. The molecular mechanisms that regulate the speed of locomotion are largely unknown. We now show that the serine/threonine kinase Akt and its activator phosphoinositide-dependent protein kinase 1 (PDK1) regulate the speed of locomotion of mouse neocortical neurons through the cortical plate. Inactivation of the PDK1-Akt pathway impaired the coordinated movement of the nucleus and centrosome, a microtubule-dependent process, during neuronal migration. Moreover, the PDK1-Akt pathway was found to control microtubules, likely by regulating the binding of accessory proteins including the dynactin subunit p150(glued) Consistent with this notion, we found that PDK1 regulates the expression of cytoplasmic dynein intermediate chain and light intermediate chain at a posttranscriptional level in th...
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.