Orphan nuclear receptor RORα-deficient mice display the cerebellar defects of staggerer

Abstract

It has recently been shown that the neurological mutant mouse staggerer (sg) harbors a deletion within the Rora gene that encodes the orphan nuclear receptor RORα. This deletion removes an exon encoding part of the ligand binding domain of the putative receptor, generating an RORα truncated protein (RORα(sg)). It is unknown whether sg acts as a null or highly hypomorphic allele. To address this question, we have generated a null mutation of Rora by targeted disruption of its DNA binding domain in ES cells. The Rorα+ mice are viable but display tremor, body imbalance, small size and die between 3-4 weeks, similar to the sg mouse. Histological examination of the cerebellum of Rorα+ and sg mice showed similar defects, including small size and fewer ectopically localized Purkinje cells. Northern blot analysis of cerebellar RNA showed that RORα transcripts are still expressed in the Rorα+ and sg mutants, although with altered mobilities. However, the cerebellum of the Rorα+ mutant does not express the RORα protein. Attempts to complement the defect of the Rorα+ with sg failed, demonstrating conclusively that the sg defects are caused by the absence of functional RORα.