Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip.
The deep cerebellar nuclei (DCN) are the main output centers of the cerebellum, but little is known about their development. Using transcription factors as cell type-specific markers, we found that DCN neurons in mice are produced in the rhombic lip and migrate rostrally in a subpial stream to the nuclear transitory zone (NTZ). The rhombic lip-derived cells express transcription factors Pax6, Tbr2, and Tbr1 sequentially as they enter the NTZ. A subset of rhombic lip-derived cells also express reelin, a key regulator of Purkinje cell migrations. In organotypic slice cultures, the rhombic lip was necessary and sufficient to produce cells that migrate in the subpial stream, enter the NTZ, and express Pax6, Tbr2, Tbr1, and reelin. In later stages of development, the subpial stream is replaced by the external granular layer, and the NTZ organizes into distinct DCN nuclei. Tbr1 expression persists to adulthood in a subset of medial DCN projection neurons. In reeler mutant mice, which have a severe cerebellar malformation, rhombic lip-derived cells migrated to the NTZ, despite reelin deficiency. Studies in Tbr1 mutant mice suggested that Tbr1 plays a role in DCN morphogenesis but is not required for reelin expression, glutamatergic differentiation, or the initial formation of efferent axon pathways. Our findings reveal underlying similarities in the transcriptional programs for glutamatergic neuron production in the DCN and the cerebral cortex, and they support a model of cerebellar neurogenesis in which glutamatergic and GABAergic neurons are produced from separate progenitor compartments.
Department of Pathology (Neuropathology), University of Washington, Seattle, Washington 98104, USA.
Andrew J
AJ
Fink
Chris
C
Englund
Ray A M
RA
Daza
Diane
D
Pham
Charmaine
C
Lau
Mary
M
Nivison
Tom
T
Kowalczyk
Robert F
RF
Hevner
D000818:Animals; D001370:Axonal Transport; D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000235:genetics; D019070:Cell Lineage; D002465:Cell Movement; D002529:Cerebellar Nuclei / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004525:Efferent Pathways / Q000196:embryology / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D005865:Gestational Age; D018698:Glutamic Acid / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008856:Microscopy, Fluorescence; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D012012:Red Nucleus / Q000166:cytology / Q000196:embryology; D000091042:Reelin Protein; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D012249:Rhombencephalon / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; C491198:Eomes protein, mouse; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D000091042:Reelin Protein; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D014157:Transcription Factors; D018698:Glutamic Acid; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases