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Phenotypic and genetic analysis of the cerebellar mutant tmgc26 , a new ENU‐induced ROR‐alpha allele
Author(s) -
Swanson Douglas J.,
Steshina Ekaterina Y.,
Wakenight Paul,
Aldinger Kimberly A.,
Goldowitz Dan,
Millen Kathleen J.,
Chizhikov Victor V.
Publication year - 2010
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2010.07330.x
Subject(s) - biology , purkinje cell , mutant , genetics , cerebellar ataxia , nonsense mutation , mutation , microbiology and biotechnology , cerebellum , gene , ataxia , missense mutation , neuroscience
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.