RORα Regulates Multiple Aspects of Dendrite Development in Cerebellar Purkinje Cells In Vivo.
The establishment of cell-type-specific dendritic arbors is fundamental for proper neural circuit formation. Here, using temporal- and cell-specific knock-down, knock-out, and overexpression approaches, we show that multiple aspects of the dendritic organization of cerebellar Purkinje cells (PCs) are controlled by a single transcriptional factor, retinoic acid-related orphan receptor-alpha (RORα), a gene defective in staggerer mutant mice. As reported earlier, RORα was required for regression of primitive dendrites before postnatal day 4 (P4). RORα was also necessary for PCs to form a single Purkinje layer from P0 to P4. The knock-down of RORα from P4 impaired the elimination of perisomatic dendrites and maturation of single stem dendrites in PCs at P8. Filopodia and spines were also absent in these PCs. The knock-down of RORα from P8 impaired the formation and maintenance of terminal dendritic branches of PCs at P14. Finally, even after dendrite formation was completed at P21, RORα was required for PCs to maintain dendritic complexity and functional synapses, but their mature innervation pattern by single climbing fibers was unaffected. Interestingly, overexpression of RORα in PCs at various developmental stages did not facilitate dendrite development, but had specific detrimental effects on PCs. Because RORα deficiency during development is closely related to the severity of spinocerebellar ataxia type 1, delineating the specific roles of RORα in PCs in vivo at different time windows during development and throughout adulthood would facilitate our understanding of the pathogenesis of cerebellar disorders. Significance statement: The genetic programs by which each neuron subtype develops and maintains dendritic arbors have remained largely unclear. This is partly because dendrite development is modulated dynamically by neuronal activities and interactions with local environmental cues in vivo. In addition, dendrites are formed and maintained by the balance between their growth and regression; the effects caused by the disruption of transcription factors during the early developmental stages could be masked by dendritic growth or regression in the later stages. Here, using temporal- and cell-specific knock-down, knock-out, and overexpression approaches in vivo, we show that multiple aspects of the dendritic organization of cerebellar Purkinje cells are controlled by a single transcriptional factor, retinoic acid-related orphan receptor alpha.
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan.
Yukari H
YH
Takeo
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan.
Wataru
W
Kakegawa
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan.
Eriko
E
Miura
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan myuzaki@a5.keio.jp.
Michisuke
http://orcid.org/0000-0002-5750-3544
M
Yuzaki
D000818:Animals; D003712:Dendrites / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008818:Mice, Neurologic Mutants; D055495:Neurogenesis; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism*
D057094:Nuclear Receptor Subfamily 1, Group F, Member 1
Purkinje cell; dendrite; migration; retinoic acid-related orphan receptor a; staggerer