title: Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter.
abstract: Unipolar brush cells (UBCs) are glutamatergic interneurons in the cerebellar cortex and dorsal cochlear nucleus. We studied the development of UBCs, using transcription factor Tbr2/Eomes as a marker for UBCs and their progenitors in embryonic and postnatal mouse cerebellum. Tbr2+ UBCs appeared to migrate out of the upper rhombic lip via two cellular streams: a dorsal pathway into developing cerebellar white matter, where the migrating cells dispersed widely before entering the internal granular layer, and a rostral pathway along the cerebellar ventricular zone toward the brainstem. Ablation of the rhombic lip in organotypic slice cultures substantially reduced the production of Tbr2+ UBCs. In coculture experiments, Tbr2+ UBCs migrated from rhombic lip explants directly into the developing white matter of adjacent cerebellar slices. The origin of Tbr2+ UBCs was confirmed by colocalization with beta-galactosidase expressed from the Math1 locus, a molecular marker of rhombic lip lineages. Moreover, the production of Tbr2+ UBCs was Math1 dependent, as Tbr2+ UBCs were severely reduced in Math1-null cerebellum. In reeler mutant mice, Tbr2+ UBCs accumulated near the rhombic lip, consistent with impaired migration through developing white matter. Our results suggest that UBCs arise from the rhombic lip and migrate via novel pathways to their final destinations in the cerebellum and dorsal cochlear nucleus. Our findings support a model of cerebellar neurogenesis, in which glutamatergic and GABAergic neurons are produced from separate progenitor pools located mainly in the rhombic lip and the cerebellar ventricular zone, respectively.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98104, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Englund
authors.forename: Tom
authors.initials: T
authors.lastname: Kowalczyk
authors.forename: Ray A M
authors.initials: RA
authors.lastname: Daza
authors.forename: Avner
authors.initials: A
authors.lastname: Dagan
authors.forename: Charmaine
authors.initials: C
authors.lastname: Lau
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Rose
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hevner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000196:embryology* / Q000502:physiology*; D007395:Interneurons / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D009413:Nerve Fibers, Myelinated / Q000502:physiology / Q000648:ultrastructure*; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology* / Q000502:physiology*