THE STRUCTURAL INTEGRITY OF ROR-ALPHA ISOFORMS IS MUTATED IN STAGGERER MICE - CEREBELLAR COEXPRESSION OF ROR-ALPHA-1 AND ROR-ALPHA-4

The recessive mouse mutation staggerer (sg) disturbs the normal develo pment of cerebellar Purkinje cells and affects certain functions of th e immune system. To identify the causative gene, we constructed high-r esolution genetic and physical maps of the staggerer locus on mouse ch romosome 9. The transcription unit of the orphan nuclear receptor ROR alpha was identified in the critical interval. Our mutational analysis confirms a recent report that the sg phenotype may be caused by a gen omic deletion in the common coding region of the ROR alpha isoforms. O f the four different isoforms of the ROR alpha gene that are generated by a combination of alternative promoter usage and exon splicing that differ in their DNA-binding properties, isoforms ROR alpha 1 and ROR alpha 4 are specifically coexpressed in the murine cerebellum and huma n cerebellum. Thus, at least two isoforms of the murine ROR alpha gene are affected by the genomic deletion associated with the staggerer ph enotype. Our finding of cerebellum-specific coregulation suggests that distinct sets of target genes regulated by the ROR alpha 1 and ROR al pha 4 isoforms are required for Purkinje cell development. (C) 1997 Ac ademic Press.