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The Journal of Neuroscience, September 6, 2006, 26(36):9184-9195; doi:10.1523/JNEUROSCI.1610-06.2006

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Development/Plasticity/Repair
Unipolar Brush Cells of the Cerebellum Are Produced in the Rhombic Lip and Migrate through Developing White Matter

Chris Englund,¹ Tom Kowalczyk,¹ Ray A. M. Daza,¹ Avner Dagan,¹ Charmaine Lau,¹ Matthew F. Rose,⁴ and Robert F. Hevner^1,2,3

¹Department of Pathology, ²Institute for Stem Cell and Regenerative Medicine, and ³Center on Human Development and Disability, University of Washington, Seattle, Washington 98104, and ⁴Program in Developmental Biology, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Dr. Robert Hevner, Harborview Medical Center, Box 359791, 325 Ninth Avenue, Seattle, WA 98104. Email: rhevner{at}u.washington.edu

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 -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.

Key words: Eomes; GluR2; Math1; Pax6; reeler; Tbr2

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Received Dec. 6, 2005; revised July 14, 2006; accepted Aug. 1, 2006.

Correspondence should be addressed to Dr. Robert Hevner, Harborview Medical Center, Box 359791, 325 Ninth Avenue, Seattle, WA 98104. Email: rhevner{at}u.washington.edu

This article has been cited by other articles:

				B. Carletti and F. Rossi Neurogenesis in the Cerebellum Neuroscientist, February 1, 2008; 14(1): 91 - 100. [Abstract] [PDF]

				R. A.M. Daza, C. Englund, and R. F. Hevner Organotypic Slice Culture of Embryonic Brain Tissue CSH Protocols, December 1, 2007; 2007(24): pdb.prot4914 - pdb.prot4914. [Abstract] [Full Text]

				M. Pascual, I. Abasolo, A. Mingorance-Le Meur, A. Martinez, J. A. Del Rio, C. V. E. Wright, F. X. Real, and E. Soriano Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression PNAS, March 20, 2007; 104(12): 5193 - 5198. [Abstract] [Full Text] [PDF]

				K. Leto, B. Carletti, I. M. Williams, L. Magrassi, and F. Rossi Different Types of Cerebellar GABAergic Interneurons Originate from a Common Pool of Multipotent Progenitor Cells. J. Neurosci., November 8, 2006; 26(45): 11682 - 11694. [Abstract] [Full Text] [PDF]

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