The structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4.
The recessive mouse mutation staggerer (sg) disturbs the normal development of cerebellar Purkinje cells and affects certain functions of the immune system. To identify the causative gene, we constructed high-resolution genetic and physical maps of the staggerer locus on mouse chromosome 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 genomic deletion in the common coding region of the ROR alpha isoforms. Of 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 alpha1 and ROR alpha4 are specifically coexpressed in the murine cerebellum and human cerebellum. Thus, at least two isoforms of the murine ROR alpha gene are affected by the genomic deletion associated with the staggerer phenotype. Our finding of cerebellum-specific coregulation suggests that distinct sets of target genes regulated by the ROR alpha1 and ROR alpha4 isoforms are required for Purkinje cell development.
Matysiak-Scholze
U
U
German Cancer Research Center (DKFZ), Heidelberg.
Nehls
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M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002874:Chromosome Mapping; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011689:Purkinje Cells / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D018076:DNA, Complementary; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; C078716:ROR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors