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Ezh2 Orchestrates Topographic Migration and Connectivity of Mouse Precerebellar Neurons

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Science  11 Jan 2013:
Vol. 339, Issue 6116, pp. 204-207
DOI: 10.1126/science.1229326

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Destination Specificity

During brain development, some types of neurons migrate from where they are born to their final functional locations. Some neurons migrate radially, from the inside to the outside, while others migrate tangentially. Di Meglio et al. (p. 204) analyzed the migration of a group of tangentially migrating neurons in the hindbrain. Although these neurons all entered the same migratory stream, they each retained positional information such that their relative organization in the destination site reflected their original organization. Interactions between epigenetic signals and the genes encoding Hox transcription factors encoded the positional information and fine-tuned migration.

Abstract

We investigated the role of histone methyltransferase Ezh2 in tangential migration of mouse precerebellar pontine nuclei, the main relay between neocortex and cerebellum. By counteracting the sonic hedgehog pathway, Ezh2 represses Netrin1 in dorsal hindbrain, which allows normal pontine neuron migration. In Ezh2 mutants, ectopic Netrin1 derepression results in abnormal migration and supernumerary nuclei integrating in brain circuitry. Moreover, intrinsic topographic organization of pontine nuclei according to rostrocaudal progenitor origin is maintained throughout migration and correlates with patterned cortical input. Ezh2 maintains spatially restricted Hox expression, which, in turn, regulates differential expression of the repulsive receptor Unc5b in migrating neurons; together, they generate subsets with distinct responsiveness to environmental Netrin1. Thus, Ezh2-dependent epigenetic regulation of intrinsic and extrinsic transcriptional programs controls topographic neuronal guidance and connectivity in the cortico-ponto-cerebellar pathway.

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