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 ROR alpha. This deletion removes an exon encoding part of the ligand binding domain of the putative receptor, generating an ROR alpha truncated protein (ROR alpha(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 Rora-/- 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 Rora-/- and sg mice showed similar defects, including small size and fewer ectopically localized Purkinje cells. Northern blot analysis of cerebellar RNA showed that ROR alpha transcripts are still expressed in the Rora-/- and sg mutants, although with altered mobilities. However, the cerebellum of the Rora-/- mutant does not express the ROR alpha protein. Attempts to complement the defect of the Rora-/- with sg failed, demonstrating conclusively that the sg defects are caused by the absence of functional ROR alpha.

The expression pattern of nuclear receptors during cerebellar development

“…Their temporal expression patterns suggest they are more likely to be important in cerebellar development. The observed ROR␣ expression pattern at the different stages we examined was not surprising, since it was previously reported that this receptor plays a crucial role in the cerebellum development such as Purkinje cell differentiation and maturation (Dussault et al, 1998;Steinmayr et al, 1998;Gold et al, 2003). Except for ROR␣, the detailed expression pattern of COUP-TFI, COUP-TFII, GCNF, ERR␥, and LRH-1 in the cerebellum, however, was not known before this study.…”

“…Mice with staggerer were found to carry a deletion within the ROR␣ gene that blocks Purkinje cells differentiation, resulting in congenital ataxia and cerebellar hypoplasia (Sidman et al, 1962;Dussault et al, 1998), and ROR␣ knockout mice show phenotypes similar to those seen with staggerer mice (Dussault et al, 1998;Steinmayr et al, 1998;Gold et al, 2003). Given these phenotypes, we next systematically analyzed the ROR␣ expression pattern in the cerebellum during different developmental stages.…”

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

“…The orphan receptor ROR␣ (31) is directly involved in regulating cerebellar development, as ROR␣-null (staggerer) mice display Purkinje cell depletion and cerebellar ataxia (74,77). In the cerebellum, both Hr (31) and VDR (78) are abundantly expressed in granule cells; therefore, in granule cells the presumed protein complex may influence cerebellar development and/or function.…”

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

“…For example, Nurr1, a member of the Nurr1/Nur77/Nor1 subfamily of receptors, appears to be essential for the migration, differentiation, and survival of dopaminergic neurons of the ventral mesencephon (Zetterstrom et al, 1997;Saucedo-Cardenas et al, 1998;Le et al, 1999;Wallen et al, 1999). Similarly, the orphan nuclear receptor RORα is crucial for maturation and survival of Purkinje cells in the cerebellum (Dussault et al, 1998;Chu and Zingg, 1999;Vogel et al, 2000). Finally, the inhibitory orphan receptor, COUP-TFI, is known to mediate neocortex identity as suggested by the loss of regional organization and specific gene expression in the absence of COUP-TFI function (Zhou et al, 2001).…”