Disorders of neuronal migration

Neuronal migration constitutes one of the major processes by which the central nervous system takes shape. Detailed knowledge about this important process now exists for different brain regions in rodent and monkey models as well as in the human. In the human, distinct genetic, chromosomal and environmental causes are known that affect neuronal migration, often in a morphologically distinct pattern, but the underlying pathological mechanisms are largely unknown. This review is intended to integrate our basic knowledge of the field with the accumulated intelligence on a large number of disorders and syndromes that represent the human part of the story.     

Pallister-Mosaic syndrome and neuronal migration disorder

We diagnosed Pallister-Mosaic syndrome (PMS) in a 4-month-old female infant. In addition to the presence of non-specific anomalies, involving anorectal, finger and ear anomalies, characteristic cranio-facial features and irregular skin lesions that appeared after age 2 months suggested the possibility of genetic mosaicism, PMS in particular. Fluorescence in situ hybridization technique revealed an extra copy of chromosome 12p; i (12p) in 30% of cultured skin fibroblasts. When focal skin lesions accompany neurodevelopmental disabilities in early infancy, genetic analysis for mosaicism should be considered for differential diagnosis. Significantly, we describe several phenotypic features and neuroimaging findings of the PMS in the present case, which have not been described in previous reports. The neuroimaging abnormalities we encountered, such as polymicrogyria, speculating congenital brain anomaly, may explain the severe motor and intellectual disabilities of PMS.     

Ubiquitin-immunoreactive granular inclusions in neuronal migration disorders

This report describes novel ubiquitin-immunoreactive inclusions in neurons in 3 out of 27 patients with neuronal migration disorders (NMDs). One patient was pathologically diagnosed as having cortical microdysgenesis, and the other two were consistent to have polymicrogyria. The inclusions were present in the perikaryon as compact granular structures, 0.5–2 μm in diameter. Since ubiquitin acts as a cellular scavenger and has a crucial role in selective protein degradation, the presence of ubiquitin-immunoreactive inclusions suggests that altered or abnormal proteins may accumulate in neurons in NMDs, although the nature of accumulated proteins remains unknown. Received: 11 September 1996 / Revised: 9 December 1996     

Regulated formation and selection of neuronal processes underlie directional guidance of neuronal migration

Axon guidance and neuronal migration are critical features of neural development, and it is believed that extracellular gradients of secreted guidance cues play important roles in pathfinding. It has been well documented that the growth cones of extending axons respond to such extracellular gradients by growing toward or away from the source of the secreted cue via asymmetrical extension of a single growth cone. However, it is unclear whether migrating neurons change direction in response to guidance molecules using the same mode of turning as extending axons. In this study, we demonstrate that migrating neurons turn away from the chemo-repellent Slit through repeated rounds of process extension and retraction and do not turn through the reorientation of a single growth cone. We further show that Slit increases the rate of somal process formation and that these processes form preferentially on the side of the cell body furthest away from the Slit source. In addition, Slit causes cell turning through asymmetric process selection. Finally, we show that multiple types of migrating neurons employ this mode of cell turning in response to a variety of guidance cues. These results show that migrating neurons employ a unique type of turning when faced with secreted guidance cues that is distinct from the type employed by axons.     

Early occurring neuronal migration and maturation disorders

This case report presents severe malformations of the central nervous system as a result of a pathological process occurring very early during development. Abnormal maturation and migration of neuroblasts were seen in all cerebral structures. Such changes are most often genetically determined, but in our case the analysis of their aetiology was not available.     

Causes of neuronal heterotopia other than migration disturbances

A differentiated form of cerebellocortical fragments (case 1) in the white matter or even in the cerebellar dentate nucleus, found in a fetus with trisomy 13, may be due to an auto‐transplantation accompanied by a penetrating vessel. A similar condition was observed in the Ammon’s horn (case 2) incidentally as a heterotopic tissue fragment of the dentate fascia. Further cause of heterotopia may be speculated as a mechanical separation by a surrounding and developing tissue part in case of organized, differentiated cerebellocortical heterotopia in the white matter (cases 3–5) which were clinically silent. Migration disturbances are not the only cause of neuronal heterotopia since the structure of heterotopia is differentiated and organized by tissue components.     

Patterns of neuronal migration in the embryonic cortex

Real-time imaging of migrating neurons has changed our understanding of how newborn neurons reach their final positions in the developing cerebral cortex. The migratory routes and modes of migration are more diverse and complex than previously thought. The finding that cortical interneurons migrate to the cortex from origins in the ventral telencephalon has already markedly altered our view of cortical migration. More recent findings have demonstrated additional nuances in the migratory pattern and highlighted differences between subsets of interneurons. Moreover, radial migration of pyramidal neurons does not progress smoothly from ventricle to cortical plate, but is instead characterized by distinct migratory phases in which neurons change shape and direction of movement. Integrating these findings with the molecular machinery underlying migration will provide a more complete picture of how the cerebral cortex is assembled.     

Wandering neuronal migration in the postnatal vertebrate forebrain

Most non-mammalian vertebrate species add new neurons to existing brain circuits throughout life, a process thought to be essential for tissue maintenance, repair, and learning. How these new neurons migrate through the mature brain and which cues trigger their integration within a functioning circuit is not known. To address these questions, we used two-photon microscopy to image the addition of genetically labeled newly generated neurons into the brain of juvenile zebra finches. Time-lapse in vivo imaging revealed that the majority of migratory new neurons exhibited a multipolar morphology and moved in a nonlinear manner for hundreds of micrometers. Young neurons did not use radial glia or blood vessels as a migratory scaffold; instead, cells extended several motile processes in different directions and moved by somal translocation along an existing process. Neurons were observed migrating for ～2 weeks after labeling injection. New neurons were observed to integrate in close proximity to the soma of mature neurons, a behavior that may explain the emergence of clusters of neuronal cell bodies in the adult songbird brain. These results provide direct, in vivo evidence for a wandering form of neuronal migration involved in the addition of new neurons in the postnatal brain.     

The multipolar stage and disruptions in neuronal migration

The genetic basis is now known for several disorders of neuronal migration in the developing cerebral cortex. Identification of the cellular processes mediated by the implicated genes is revealing crucial stages of neuronal migration and has the potential to reveal common cellular causes of neuronal migration disorders. We hypothesize that a newly recognized morphological stage of neuronal migration, the multipolar stage, is vulnerable and is disrupted in several disorders of neocortical development. The multipolar stage occurs as bipolar progenitor cells become radially migrating neurons. Several studies using in utero electroporation and RNAi have revealed that transition out of the multipolar stage depends on the function of filamin A, LIS1 and DCX. Mutations in the genes encoding these proteins in humans cause distinct neuronal migration disorders, including periventricular nodular heterotopia, subcortical band heterotopia and lissencephaly. The multipolar stage therefore seems to be a critical point of migration control and a vulnerable target for disruption of neocortical development. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).     

Astroglia and microglia in cerebellar neuronal migration disturbances

Between the neuronal and glial cells there is a close relationship conditioning a tight morphological correlation and proper functional interplay. Disturbed interaction between glial and neuronal components leads to inappropriate neural circuits. The reflection of the failure of neural circuit organisation is the picture of morphological changes of neurons and glia. The appearance of microglia and astroglia was analysed in a defectively formed cellular network due to cerebellar neuronal migration disturbances. Focal disruption of neuron migration leads to their differentiation in an abnormal position manifested as heterotopias and cortical anomalies. Neurons that had lost their proper migratory way and heterotopically settled in the white matter were encircled by GFAP-positive astrocytes, with morphology appropriate for surrounding white matter. The microglial cells infiltrated the parenchyma within the heterotopic neurons playing a role in their elimination. In the cerebellar cortical malformations astrocytes were grouped near the Purkinje cells. In the minimal cortical dysplasia the increased number of astrocytes supported the neurons. Impaired morphological components of the glial-pial barrier were observed. In the massive cortical malformations a few degenerated astrocytes followed the disarranged Purkinje cells, while microglia and Bergmann glia fibres were not present. Absence of cells supporting and organizing the cerebellar cortex had an effect on loss of Purkinje cell shape, their disorientation and abnormal position. The appearance and localisation of the astroglia and microglia in the abnormal cerebellar circuitry due to migration disturbances is dependent on the pathomechanism of the anomalies.     

Epilepsia partialis continua and neuronal migration anomalies.

Neuronal migration anomalies commonly cause seizures that are partial in type and generally refractory to medical treatment. Epilepsia partialis continua (EPC), an unusual form of epilepsy commonly related to acute damage of the cerebral cortex or to a chronic lesion, has never been described in a patient with neuronal migration anomalies. In 50 children with epilepsy due to neuronal migration anomalies, we observed two cases of EPC. These two children had unilateral neuronal migration abnormalities with partial seizures other than EPC and contralateral hemiparesis. Epilepsia partialis continua appeared two to three years after the onset of partial attacks and was accompanied by a worsening of the children's previous hemiparesis. Although a rare seizure manifestation in children with neuronal migration anomalies, when it does appear, EPC can aggravate the clinical neurological condition and should always be investigated for in these cases. Because its clinical appearance is often subtle, as in these two children, EPC may easily remain undiagnosed.     

Novel forms of neuronal migration in the rat cerebellum

Infrared video microscopy of neonatal rat cerebellum (P0-P14) was used to directly visualize migrating granule neurons in relation to other cerebellar cells in a brain slice for up to 24 hr. Initially (P0-P5), granule neurons move along radial migration pathways of other neuronal fibers. These pathways are probably established by the bipolar granule neurons that attach to the external basement membrane via one process and extend another process toward the Purkinje cell layer. At P5-P8, a substantial number of granule neurons move horizontally and extend long parallel fibers. Both radially and horizontally migrating granule neurons move by nuclear translocation inside their preformed processes with a speed that varies between 6 and 120 μ/hr. In P10-P12 animals, the horizontally oriented granule neurons start to migrate radially. They move into the internal granule cell layer either along the radial pathways of other neuronal fibers or in contact with the matured glial processes. The radial neuronal migration pathways disappear by P14 whereas the glial cell processes are maintained and reach the basal lamina. These results describe novel radial and horizontal modes of neuronal migration that proceed independently of the physical glial guidance. © 1995 Wiley-Liss, Inc.     

Failure of prosencephalic unfolding and neuronal migration in acardia

Acardia is a fatal complication of twin pregnancy. It is caused by a retrograde flow of arterial blood from a pump into an acardiac twin through placental arterial and venous connections. The heart function of the recipient twin is either blocked or insufficient to support perfusion of the upper body. Severe developmental anomalies ensue. While most acardiacs are anencepahalic, a few twins with a rudimental heart (hemicardiac) are able to support a variably complex brain. Here we report three cases of hemicardiac twinning with neuronal migrational defects. The most severe abnormalities affected the supratentorial compartment. They can be conceptually divided in two groups. The first, which we tentatively linked to agenesis of the choroid plexus, can be described as a failure of prosencephalic unfolding. The resulting defects included collapsed neocortex, agenesis of the hippocampi and scrambled basal ganglia and diencephalon. The second group of lesions can be theoretically deduced to a result of disruption of the glia-pial boundary with subsequent formation of leptomeningeal heterotopia and zona cerebrovasculosa. Our observations highlight that even in the milieu of a normal genetic background, severe restriction of brain perfusion could lead to neuronal migration defects. Our data also show that adequate unraveling of the brain architecture is crucially dependent on both the parenchymal vascularization and production of the cerebrospinal fluid by the choroid plexus.     

Neurotrophins and neuronal migration in the developing rodent brain

Neurotrophins are known to be key regulators of neuronal survival, differentiation, function and plasticity in the developing and adult rodent brain. A novel role for neurotrophins has been emerging from recent research, that of motogenic and chemoattractant factors for several populations of migrating neuronal precursors in the developing mouse brain. The aim of the present article is to summarize and discuss the studies that have contributed to the existing body of evidence.     

Involvement of platelet-activating factor and LIS1 in neuronal migration

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a biologically active lipid mediator. We have previously shown the expression of PAF receptor in neurons and microglia. PAF is produced in the brain from its precursor, and degraded by the enzyme PAF acetylhydrolase. LIS1 is a regulatory subunit of PAF acetylhydrolase, and is identical to a gene whose deletion causes the human neuronal migration disorder, type I lissencephaly. Indeed, Lis1 mutant mice display defects in neuronal migration and layering in vivo, and also in cerebellar granule cell migration in vitro. However, the roles of PAF and the PAF receptor in the neuronal migration remain to be determined. Here, we show that PAF receptor-deficient mice exhibited histological abnormalities in the embryonic cerebellum. PAF receptor-deficient cerebellar granule neurons migrated more slowly in vitro than wild-type neurons, consistent with the observation that a PAF receptor antagonist reduced the migration of wild-type neurons in vitro. Synergistic reduction of neuronal migration was observed in a double mutant of PAF receptor and LIS1. Unexpectedly, PAF affected the migration of PAF receptor-deficient neurons, suggesting a receptor-independent pathway for PAF action. The PAF receptor-independent response to PAF was abolished in granule neurons derived from the double mutant mice. Thus, our results suggest that the migration of cerebellar granule cells is regulated by PAF through receptor-dependent and receptor-independent pathways, and that LIS1 is a pivotal molecule that links PAF action and neuronal cell migration both in vivo and in vitro.