Elsevier

Cell Calcium

Volume 37, Issue 5, May 2005, Pages 387-393
Cell Calcium

Ca2+ transients control CNS neuronal migration

https://doi.org/10.1016/j.ceca.2005.01.006Get rights and content

Abstract

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.

Introduction

After the closing of the neural tube and the telencephalic vesicles, neuronal migration is the main process by which topical differentiation within the brain is effected [1], [2]. By this process, billions of newly generated neurons are addressed to their proper positions, mainly in nuclear masses or in the cerebral and cerebellar cortices [1], [2]. In the human, distinct genetic mutations and environmental toxins can affect neuronal migration, and result in abnormal cortical development, which is generally called neuronal migration disorder [3], [4]. Although it is still unclear how these cortical abnormalities develop, the past few years have yielded several critical advances in our understanding of the basic processes underlying neuronal migration. For example, the migration of neurons requires the orchestration of multiple molecular events, including the selection of a pathway, the formation of adhesive interactions with cellular and extracellular substrates and the assembly and disassembly of cytoskeletal components [5], [6], [7].

External cues and cell–cell contact are expected to be essential for controlling neuronal movement along the migratory pathway, but signaling mechanisms underlying this process remain to be determined. Recent studies began to indicate that Ca2+ signaling may play a key role in controlling neuronal cell migration. For example, in the developing cerebrum, neuronal precursor cells and migrating neurons exhibit spontaneous elevations in intracellular Ca2+ levels [8], [9]. Increases in intracellular Ca2+ levels by stimulating the NMDA and GABA receptors affect the migration of cortical neurons [10], [11]. Furthermore, cerebellar granule cells in culture exhibit transient elevations in intracellular Ca2+ levels, and the reduction of the amplitude and frequency components of the Ca2+ elevations results in a reversible retardation of cell movement [12]. The rate of granule cell migration in the early postnatal cerebellum is highly sensitive to alterations of the Ca2+ influx through the N-type Ca2+ channels or the NMDA receptors [13], [14]. The activation of somatostatin receptors, which reduces Ca2+ channel activity, slows down granule cell migration in the internal granular layer [15]. The local application of Slit2, which is a secreted chemorepellant for many cells, induces a change in the gradients of intracellular Ca2+ within the granule cell somata and reverses the direction of their movement [16]. Taken together, these studies suggest that Ca2+ signaling functions as a mediator for controlling the migration of immature neurons.

In this review, we will focus on the recent studies showing the role of Ca2+ transients in controlling granule cell migration in the developing cerebellum. The prenatal and early postnatal cerebella have been used as model systems of neuronal cell migration, since the defined neuronal cytoarchitecture and the small number of neuronal types in the cerebellum provide an ideal system for determining molecular and cellular mechanisms of neuronal migration [6], [7]. Specifically, the migration of cerebellar granule cells, which are the most abundant neuronal cell type in the CNS, has been intensively examined, and it has become apparent that cellular and molecular mechanisms underlying granule cell migration are utilized during the migration of immature neurons in other brain regions [5], [6], [7]. In this article, we will first describe how granule cells migrate from their birthplace to their final destination in the developing cerebellum. We will then present how Ca2+ transients control the migratory behavior of granule cells.

Section snippets

Cortical layer-specific changes in migration of cerebellar granule cell

To understand a role of Ca2+ transients in controlling granule cell migration in vivo, it is essential to first describe the major cellular events and phases of granule cell migration in the developing cerebellum. The real-time observation of cell movement in acute cerebellar slices obtained from early postnatal mice demonstrates that granule cells alter their shape concomitantly with changes in the mode and rate of migration as they traverse different cortical layers (Fig. 1A) [17], [18], [19]

Distinct patterns of Ca2+transients in granule cell somata along the migratory pathway

The combined use of confocal microscopy and Ca2+ indicator dye (Oregon Green 488 BAPTA-1) reveals that cerebellar granule cells exhibit a distinct pattern of transient Ca2+ elevations as they migrate in different cortical layers (Fig. 1B and C) [20].

Changes in Ca2+ transient frequency affect the rate of granule cell migration

The next question is whether the changes in Ca2+ transients directly control granule cell migration. Experimental modifications of the Ca2+ transient frequency have provided the answer to this question [12], [20]. Since the Ca2+ levels of granule cell somata are influenced by the amount of Ca2+ influx through the voltage-gated Ca2+ channels and the neurotransmitter-coupled ion channels, and Ca2+ release from the internal stores [5], [12], we stimulated or inhibited these potential Ca2+ sources

Loss of Ca2+ transients prior to completion of migration

At their final destination of migration, granule cells completely lose the Ca2+ transients, or significantly reduce the frequency (Fig. 1D). The loss (or reduction) of Ca2+ transients is not caused by physiological deterioration after a prolonged period of observation, because 2 and 5 h later postmigratory (stationary) granule cells resumed spontaneous Ca2+ transients (Fig. 1C). Time-lapse observation of intracellular Ca2+ levels and cell movement revealed the sequence of the loss of Ca2+

Conclusions

Recent studies demonstrate that Ca2+ transients control the rate of granule cell migration by altering their frequency [12], [20]. The loss of Ca2+ transients provides an internal signal triggering cellular cascades responsible for the completion of granule cell migration. The roles of transient Ca2+ elevations in controlling cell motility have been reported in various types of cells ranging from fibroblast to immature neurons [22], [23]. Neuronal precursors and postmigratory neurons in the

Acknowledgments

We thank Y. Komuro for critically editing the manuscript. H.K. was supported by National Institutes of Health Grant AA 13613 and Whitehall Foundation Grant 2001-12-35.

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