Biomedical subjects

Hitoshi Komuro

Publications and source records attributed to Hitoshi Komuro.

8 recordsLinked to original sources

PubMed2007

How does alcohol impair neuronal migration?

Maternal alcohol consumption during pregnancy can cause serious birth defects, of which fetal alcohol syndrome (FAS) is the most devastating. Recognized by characteristic craniofacial abnormalities and growth deficiency, this condition produces severe alcohol-induced damage in the developing brain. FAS children experience ataxia; deficits in intellectual functioning; and difficulties in learning, memory, problem solving, and attention. Multiple aspects of central nervous system development can be affected by alcohol exposure, but the most striking abnormalities are neuronal and glial migration. Little is known about cellular mechanisms by which alcohol affects the migration of immature neurons. Recently, it has been found that Ca(2+) signaling and cyclic nucleotide signaling are the central targets of the action of alcohol in neuronal cell migration. Most importantly, the aberrant migration of immature neurons caused by alcohol exposure is significantly ameliorated by controlling the activity of these second-messenger pathways. In this Mini-Review, we first describe how alcohol exposure impairs the migration of cerebellar granule cells and then discuss the signaling mechanisms involved.

Alcoholism↗

PubMed2006

Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex.

In the mammalian CNS, oligodendrocyte precursor cells (OPCs) express most neurotransmitter receptors, but their function remains unclear. The current studies suggest a physiological role for glutamate (AMPA and/or kainate) receptors in OPC migration. AMPA stimulated alphav integrin-mediated OPC migration by increasing both the rate of cell movement and the frequency of Ca2+ transients. A protein complex containing the myelin proteolipid protein (PLP) and alphav integrin modulated the AMPA-stimulated migration, and stimulation of OPC AMPA receptors resulted in increased association of the AMPA receptor subunits themselves with the alphav integrin/PLP complex. Thus, after AMPA receptor stimulation, an alphav integrin/PLP/neurotransmitter receptor protein complex forms that reduces binding to the extracellular matrix and enhances OPC migration. To assess the extent to which PLP was involved in the AMPA-stimulated migration, OPCs from the myelin-deficient (MD) rat, which has a PLP gene mutation, were analyzed. OPCs from the MD rat had a normal basal migration rate, but AMPA did not stimulate the migration of these cells, suggesting that the PLP/alphav integrin complex was important for the AMPA-mediated induction. AMPA-induced modulation of OPC migration was abolished by pertussis toxin, although baseline migration was normal. Thus, G-protein-dependent signaling is crucial for AMPA-stimulated migration of OPCs but not for basal OPC migration. Other signaling pathways involved in this AMPA-stimulated OPC migration were also determined. These studies highlight novel signaling determinants of OPC migration and suggest that glutamate could play a pivotal role in regulating integrin-mediated OPC migration.

Analysis of Variance↗

PubMed2006

Reversal of neuronal migration in a mouse model of fetal alcohol syndrome by controlling second-messenger signalings.

The brains of fetal alcohol syndrome patients exhibit impaired neuronal migration, but little is known about the mechanisms underlying this abnormality. Here we show that Ca2+ signaling and cyclic nucleotide signaling are the central targets of alcohol action in neuronal cell migration. Acute administration of ethanol reduced the frequency of transient Ca2+ elevations in migrating neurons and cGMP levels and increased cAMP levels. Experimental manipulations of these second-messenger pathways, through stimulating Ca2+ and cGMP signaling or inhibiting cAMP signaling, completely reversed the action of ethanol on neuronal migration in vitro as well as in vivo. Each second messenger has multiple but distinct downstream targets, including Ca2+/calmodulin-dependent protein kinase II, calcineurin, protein phosphatase 1, Rho GTPase, mitogen-activated protein kinase, and phosphoinositide 3-kinase. These results demonstrate that the aberrant migration of immature neurons in the fetal brain caused by maternal alcohol consumption may be corrected by controlling the activity of these second-messenger pathways.

Animals↗

PubMed2005

Ca2+ transients control CNS neuronal migration.

In the developing CNS, postmitotic neurons exhibit dynamic changes in the mode, direction and rate of migration as they traverse different cortical layers, but the mechanisms underlying this process is largely unknown. Recent studies show that the changes in Ca2+ transient frequency play a central role in controlling the neuronal cell migration in a cortical layer-specific manner. In this article, we will first describe how granule cells migrate through different terrains of the developing cerebellar cortex. We will then present how such migration of granule cells is controlled by altering the Ca2+ transient frequency in their somata. Finally, we will discuss how the loss of Ca2+ transients triggers the completion of granule cell migration at their final destination.

Animals↗

PubMed2004

Completion of neuronal migration regulated by loss of Ca(2+) transients.

The migration of immature neurons constitutes one of the major processes by which the central nervous system takes shape. Completing the migration at the final destination requires the loss of cell body motility, but little is known about the signaling mechanisms underlying this process. Here, we show that a loss of transient Ca(2+) elevations triggers the completion of cerebellar granule cell migration. Simultaneous observation of the intracellular Ca(2+) levels and cell movement in cerebellar slices of the early postnatal mice revealed that granule cells exhibit distinct frequencies of the transient Ca(2+) elevations as they migrate in different cortical layers, and complete the migration only after the loss of Ca(2+) elevations. The reduction of the Ca(2+) elevation frequency by decreasing Ca(2+) influx, or by inhibiting the activity of phospholipase C, PKC, or Ca(2+)/calmodulin, halted the granule cell movement prematurely. In contrast, increasing the Ca(2+) elevation frequency by increasing Ca(2+) release from internal stores, or by elevating intracellular cAMP levels, significantly delayed the completion of granule cell migration. The timing of the loss of Ca(2+) elevations was intrinsically set in the granule cells and influenced by external cues. These results suggest that Ca(2+) signaling, dictated by multiple signaling systems, functions as a mediator for completing the migration of immature neurons.

Animals↗

PubMed2003

Cellular and molecular mechanisms of cerebellar granule cell migration.

The real-time observation of cell movement in brain slice preparations reveals that in the developing brain, postmitotic neurons alter their shape concomitantly with changes in the mode, direction, tempo, and rate of migration as they traverse different cortical layers. Although it has been hypothesized that orchestrated activities of multiple external cues and cell-cell contact are essential for controlling the cortical-layer-specific changes in cell migration, signaling mechanisms and external guidance cues related to the alteration of neuronal cell migration remain to be determined. In this article, we will first review recent studies on position-specific changes in granule cell behavior through different migratory terrains of the developing cerebellar cortex. We will then present possible roles for the coordinated activity of Ca2+ channels, NMDA type of glutamate receptors, and intracellular Ca2+ fluctuations in controlling cerebellar granule cell movement. Furthermore, we will discuss the crucial roles of brain-derived neurotrophic factor (BDNF), neuregulin (NRG), stromal cell-derived factor 1alpha (SDF-1alpha), ephrin-B2, and EphB2 receptor in providing directional cues promoting granule cell migration from the external granular layer (EGL) to the internal granular layer (IGL). Finally, we will demonstrate that endogenous somatostatin controls the migration of granule cells in a cortical layer-specific manner: Endogenous somatostatin accelerates granule cell movement near the birthplace within the EGL, but significantly slows down the movement near their final destination within the IGL.

Animals↗

PubMed2002

Intrinsic program for migration of cerebellar granule cells in vitro.

Cerebellar granule cells exhibit distinct modes of migration in different cortical layers. The role of external cues in controlling these alterations has been suggested, but the significance of internal programs is not well understood. In the present study, we examined autonomous changes of migratory behavior of isolated granule cells in microexplant cultures of the postnatal mouse cerebellum. We found that isolated granule cells sequentially go through three characteristic phases of migration without cell-cell contact. In the first phase (0-20 hr in vitro) granule cells exhibit the highest rate of turning behavior and have multiple short processes. The length of the movement cycle is shortest. In the second phase (20-40 hr in vitro), granule cells extend a long and thick process and exhibit an elongated cycle of movement. Their speed is fastest, whereas the rate of turning is lowest. In the third phase (40-60 hr in vitro), granule cells slow down their movement and slightly increase their turnings. The length of the movement cycle further increases. At the end, the cells become permanently stationary, extend a lamellipodium around the soma, and emit several thin processes. Interestingly, granule cells sequentially develop four different modes of turning. These results indicate that internal (intrinsic) programs control alterations of granule cell behavior in a stage-dependent manner, suggesting that such programs independent of local cell-cell contacts may be essential for granule cell translocation in the developing cerebellum.

Animals↗

PubMed2002

Stage-specific control of neuronal migration by somatostatin.

Developing neurons transiently express somatostatin and its receptors, but little is known about their function at these early stages. As we thought that endogenous somatostatin might control the migratory behaviour of immature neurons, we have examined the effects of somatostatin in cerebellar granule cells of early postnatal mice, because these cells express all five types of somatostatin receptors before the initiation of their migration. Here we show that somatostatin has opposite and stage-specific effects on the migration of cerebellar granule cells. Activation of somatostatin receptors increases the rate of granule cell migration near their birthplace, but decreases the rate near their final destination. Furthermore, somatostatin enhances the size and frequency of spontaneous Ca2+ fluctuations in the early phase of migration, whereas it eliminates spike-like Ca2+ transients in the late phase. Somatostatin-induced changes at both early and late phases are reversed by a blockade of K+ channel activity. These results indicate that somatostatin may provide an essential cue for accelerating the movement of granule cells in the early phase and for terminating the movement in the late phase through altering intracellular Ca2+ concentrations and K+ channel activity.

Animals↗