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Hironori Wada


I am interested in how animals adapt themselves to their environments. Many animals (birds, fish, etc) travel long distances and face different environments during their migration. They adapt themselves to different temperatures, climates, foods, etc, and they succeed in producing offspring. We can expect the same things happen to the migrating neurons within the brain. During their migration, the neurons have to respond correctly to their environments, such as different guidance cues and cell adhesion molecules. In this study, by identifying novel genes required for the neuronal migration, I want to reveal how the migrating neurons adapt themselves to the surrounding neuroepithelial environments. The molecular basis underlying the plasticity of the neuronal migration may give us insights on how animal species evolved by responding to their environmental changes.

The neuroepithelial cells exclude the facial motor neuron by expression of planar cell polarity (PCP) genes

Migration of immature neurons from their site of origin to their final destination is a crucial step in the development of the vertebrate nervous system. Many neurons migrate tangentially through one cell layer at a specific depth within the brain. Some neurons migrate through the subventricular region (e.g., the GABAergic neurons into the olfactory bulb), others migrate near the pial surface (e.g., the granule cells into the cerebellar cortex), or through the intermediate zone (e.g., the GABAergic neurons into the cerebral cortex). However, the mechanisms by which neurons select specific layers as their migrating pathway remain largely unknown.

The zebrafish is a good model to address this question. In the developing hindbrain, the facial (nVII) motor neurons originate in rhombomere (r) 4 and migrate tangentially to r6 through the pial surface of the hindbrain. We used the transgenic Isl1-GFP strain, which expresses green fluorescent protein (GFP) in the hindbrain motor neurons, and identified three novel mutants with disrupted migration of the nVII motor neurons (Fig.1).

We showed that these three genes encode a cytoplasmic protein Scribble1, planar cell polarity (PCP) pathway proteins Celsr2 and Frizzled3a. We showed that expression of these genes in neuroepithelial cells maintain the nVII motor neurons near the pial surface during their caudal migration in the zebrafish hindbrain. Mosaic analyses show that expression of the frizzled3a gene in the surrounding neuroepithelial cells prevented the entry of the nVII motor neurons in the neuroepithelial layer. These results indicate that neuroepithelial cells have a role in excluding differentiated neurons from the neuroepithelial layer, and this function is mediated by conserved PCP pathway signaling (Fig. 2). Our findings may provide new insights into the general mechanisms underlying formation of the layered structures in the mammalian brain, such as in the cerebral cortex.