Abstract
During corticogenesis, neuronal migration is an essential step for formation of a functional brain, and abnormal migration is known to cause various neurological disorders. Neuronal migration is not just a simple movement of the cell body, but a consequence of various morphological changes and coordinated subcellular events. Recent advances in in vivo and ex vivo cell biological approaches, such as in utero gene transfer, slice culture and ex vivo chemical inhibitor techniques, have revealed details of the morphological and molecular aspects of neuronal migration. Migrating neurons have been found to have a unique structure, dilation or swelling, at the proximal region of the leading process; this structure is not found in other migrating cell types. The formation of this structure is followed by nuclear deformation and forward movement, and coordination of this three-step sequential morphological change (the dilation/swelling formation, nuclear elongation and nuclear movement) is essential for proper neuronal migration and the construction of a functional brain structure. In this review, we will introduce the morphological features of this unique structure in migrating neurons and summarize what is known about the molecules regulating the dilation/swelling formation and nuclear deformation and movement.
Highlights
One of the pronounced morphological features of the mammalian cerebral cortex is the six-layer structure composed of different neural cell types
While p27kip1 is a CDK inhibitory protein and controls G1 length and cell cycle exit in the nucleus [41,42,43], recent studies have indicated that p27kip1 functions in cytoplasm to regulate both actin and microtubule organization [22,26]. It is unclear which downstream event(s) of p27kip1 is important for the dilation formation, Cyclin-dependent kinase 5 (Cdk5) is thought to regulate both actin cytoskeleton and microtubules. This is because suppression of Cdk5 results in a decrease of actin accumulation at the dilation as well as perturbation of the Golgi positioning, which largely depends on microtubules and dynein motor activity, in the locomoting neurons [13]
While JNK does not affect the cross-sectional area of the cytoplasmic dilation, knockdown of JNK suppresses the nuclear elongation (Figure 3), suggesting that Cdk5 and JNK, both of which are known to control microtubule dynamics [21,30], have different roles in the locomotion mode [13]
Summary
One of the pronounced morphological features of the mammalian cerebral cortex is the six-layer structure composed of different neural cell types. Several in vitro and ex vivo techniques, allowing direct analysis of molecules involved culture [12], slice culture-based ex vivo chemical inhibitor technique [11,13], lattice culture [14,15], in the locomotion mode, have been established These include explant culture [12], slice culture-based ex vivo chemical inhibitor technique [11,13], lattice culture [14,15], co-culture of primary cortical excitatory neurons and nestin-positive cells [16], co-culture of MGE explants on dissociated cortical neurons with elongated axons [17] and cortical imprint assay [18]. The locomoting neurons that are visualized with in vivo electroporated fluorescence proteins are observed with a time-lapse microscopy and the cortical slices are treated with a chemical compound, such as an inhibitor for a molecule of interest, during the time-lapse observation Using this method, the migration speed and morphological changes of the same locomoting neurons before and after the inhibitor treatment can be analyzed. While in vivo knockdown of Fyn, a major neuronal Src kinase, disturbs the early phase of migration [11,24], treatment of cortical slice tissues with an inhibitor for Src family kinases reduces the migration speed of the locomoting neurons [11]
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