title: Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha allele.
abstract: ROR-alpha is an orphan nuclear receptor, inactivation of which cell-autonomously blocks differentiation of cerebellar Purkinje cells with a secondary loss of granule neurons. As part of our ENU mutagenesis screen we isolated the recessive tmgc26 mouse mutant, characterized by early-onset progressive ataxia, cerebellar degeneration and juvenile lethality. Detailed analysis of the tmgc26-/- cerebella revealed Purkinje cell and granule cell abnormalities, and defects in molecular layer interneurons and radial glia. Chimera studies suggested a cell-autonomous effect of the tmgc26 mutation in Purkinje cells and molecular layer interneurons, and a non-cell-autonomous effect in granule cells. The mutation was mapped to a 13-Mb interval on chromosome 9, a region that contains the ROR-alpha gene. Sequencing of genomic DNA revealed a T-to-A transition in exon 5 of the ROR-alpha gene, resulting in a nonsense mutation C257X and severe truncation of the ROR-alpha protein. Together, our data identify new roles for ROR-alpha in molecular layer interneurons and radial glia development and suggest tmgc26 as a novel ROR-alpha allele that may be used to further delineate the molecular mechanisms of ROR-alpha action.
authors: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Douglas J
authors: DJ
authors: Swanson
authors: Ekaterina Y
authors: EY
authors: Steshina
authors: Paul
authors: P
authors: Wakenight
authors: Kimberly A
authors: KA
authors: Aldinger
authors: Dan
authors: D
authors: Goldowitz
authors: Kathleen J
authors: KJ
authors: Millen
authors: Victor V
authors: VV
authors: Chizhikov
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D002678:Chimera; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008818:Mice, Neurologic Mutants; D009024:Morphogenesis / Q000235:genetics; D016296:Mutagenesis / Q000187:drug effects*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics* / Q000502:physiology; D011689:Purkinje Cells / Q000473:pathology
chemical_list: D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D005038:Ethylnitrosourea