RORalpha Coordinates Reciprocal Signaling in Cerebellar Development Through Sonic Hedgehog and Calcium-dependent Pathways

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2003 Dec 23

PMID 14687547

Citations 74

Authors

David A Gold

Sung Hee Baek

Nicholas J Schork

David W Rose

DeLaine D Larsen

Benjamin D Sachs

Michael G Rosenfeld

Bruce A Hamilton

Affiliations

Soon will be listed here.

Abstract

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

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References

Hamilton B, Frankel W, Kerrebrock A, HAWKINS T, Fitzhugh W, Kusumi K . Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature. 1996; 379(6567):736-9. DOI: 10.1038/379736a0. View

Sangameswaran L, Hempstead J, Morgan J . Molecular cloning of a neuron-specific transcript and its regulation during normal and aberrant cerebellar development. Proc Natl Acad Sci U S A. 1989; 86(14):5651-5. PMC: 297682. DOI: 10.1073/pnas.86.14.5651. View

Kenney A, Rowitch D . Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol. 2000; 20(23):9055-67. PMC: 86558. DOI: 10.1128/MCB.20.23.9055-9067.2000. View

Wallace V . Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol. 1999; 9(8):445-8. DOI: 10.1016/s0960-9822(99)80195-x. View

Landis D, Reese T . Structure of the Purkinje cell membrane in staggerer and weaver mutant mice. J Comp Neurol. 1977; 171(2):247-60. DOI: 10.1002/cne.901710208. View

Zupanc G, Clint S . Radial glia-mediated up-regulation of somatostatin in the regenerating adult fish brain. Neurosci Lett. 2001; 309(3):149-52. DOI: 10.1016/s0304-3940(01)02061-4. View

Lau P, Bailey P, Dowhan D, Muscat G . Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD. Nucleic Acids Res. 1998; 27(2):411-20. PMC: 148194. DOI: 10.1093/nar/27.2.411. View

Brault V, MOORE R, Kutsch S, Ishibashi M, Rowitch D, McMahon A . Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development. 2001; 128(8):1253-64. DOI: 10.1242/dev.128.8.1253. View

Shang Y, Myers M, Brown M . Formation of the androgen receptor transcription complex. Mol Cell. 2002; 9(3):601-10. DOI: 10.1016/s1097-2765(02)00471-9. View

10.

Landis D, Sidman R . Electron microscopic analysis of postnatal histogenesis in the cerebellar cortex of staggerer mutant mice. J Comp Neurol. 1978; 179(4):831-63. DOI: 10.1002/cne.901790408. View

11.

Hall A, LUCAS F, Salinas P . Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell. 2000; 100(5):525-35. DOI: 10.1016/s0092-8674(00)80689-3. View

12.

Goldowitz D, Hamre K . The cells and molecules that make a cerebellum. Trends Neurosci. 1998; 21(9):375-82. DOI: 10.1016/s0166-2236(98)01313-7. View

13.

Giguere V, Tini M, Flock G, Ong E, Evans R, Otulakowski G . Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994; 8(5):538-53. DOI: 10.1101/gad.8.5.538. View

14.

Nakagawa S, Watanabe M, Inoue Y . Prominent expression of nuclear hormone receptor ROR alpha in Purkinje cells from early development. Neurosci Res. 1997; 28(2):177-84. DOI: 10.1016/s0168-0102(97)00042-4. View

15.

Zupanc G . Up-regulation of somatostatin after lesions in the cerebellum of the teleost fish Apteronotus leptorhynchus. Neurosci Lett. 1999; 268(3):135-8. DOI: 10.1016/s0304-3940(99)00299-2. View

16.

Hirota J, Ando H, Hamada K, Mikoshiba K . Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1. Biochem J. 2003; 372(Pt 2):435-41. PMC: 1223404. DOI: 10.1042/BJ20030110. View

17.

Shimamura K, Hirano S, McMahon A, Takeichi M . Wnt-1-dependent regulation of local E-cadherin and alpha N-catenin expression in the embryonic mouse brain. Development. 1994; 120(8):2225-34. DOI: 10.1242/dev.120.8.2225. View

18.

Wilkinson D, Nieto M . Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol. 1993; 225:361-73. DOI: 10.1016/0076-6879(93)25025-w. View

19.

Crepel F, Delhaye-Bouchaud N, Guastavino J, Sampaio I . Multiple innervation of cerebellar Purkinje cells by climbing fibres in staggerer mutant mouse. Nature. 1980; 283(5746):483-4. DOI: 10.1038/283483a0. View

20.

Park J, Wood M, Cole M . BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol. 2002; 22(5):1307-16. PMC: 134713. DOI: 10.1128/MCB.22.5.1307-1316.2002. View