RORα Coordinates Reciprocal Signaling in Cerebellar Development through Sonic hedgehog and Calcium-Dependent Pathways

• Published in: Neuron (Cambridge, Mass.) Vol. 40; no. 6; pp. 1119 - 1131
• Main Authors: Gold, David A., Baek, Sung Hee, Schork, Nicholas J., Rose, David W., Larsen, DeLaine D., Sachs, Benjamin D., Rosenfeld, Michael G., Hamilton, Bruce A.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 18-12-2003
• Subjects: b-Catenin; orphan nuclear receptor ROR-^a; Sonic hedgehog protein
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(03)00769-4

The cerebellum provides an excellent system for understanding how afferent and target neurons coordinate sequential intercellular signals and cell-autonomous genetic programs in development. Mutations in the orphan nuclear receptor RORα block Purkinje cell differentiation with a secondary loss of afferent granule cells. We show that early transcriptional targets of RORα include both mitogenic signals for afferent progenitors and signal transduction genes required to process their subsequent synaptic input. RORα acts through recruitment of gene-specific sets of transcriptional cofactors, including β-catenin, p300, and Tip60, but appears independent of CBP. One target promoter is
Sonic hedgehog, and recombinant Sonic hedgehog restores granule precursor proliferation in RORα-deficient cerebellum. Our results suggest a link between RORα and β-catenin pathways, confirm that a nuclear receptor employs distinct coactivator complexes at different target genes, and provide a logic for early RORα expression in coordinating expression of genes required for reciprocal signals in cerebellar development.