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General Terms and Conditions

Former Name	B6.Cg-Rorasg/J    (Changed: 25-JUL-06 )
	B6.C3-Rorasg/J    (Changed: 24-JUL-06 )
	B6.C3(B10)-Rorasg/J    (Changed: 21-JUL-06 )
	B6.Cg-Rorasg/J    (Changed: 20-JUL-06 )
Genes & Alleles	Rora;   Rorasg;

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Product Information

Strain Details

Type JAX® GEMM® Strain - Congenic Additional information on JAX® GEMM® Strains. Type JAX® GEMM® Strain - Mutant Strain Mating System Heterozygote x Heterozygote         (Female x Male) PCR typed heterozygote x heterozygote Species laboratory mouse Background Strain C57BL/6J Donor Strain Mixed stock Generation NE9F63 (14-DEC-07)

Appearance
black, ataxic, tremors
Related Genotype: a/a Rora^sg/Rora^sg

black, unaffected
Related Genotype: a/a +/? or a/a Rora^sg/+

Strain Description
Mice homozygous for the staggerer spontaneous mutation (Rora^sg) show a staggering gait, mild tremor, hypotonia, and small size. The cerebellar cortex of homozygous mutant mice is grossly underdeveloped with a deficiency of granule cells and Purkinje cells. The remaining granule cells migrate inward from the external layer prematurely and then degenerate. Purkinje cells are much delayed in postnatal differentiation and lack the dendritic spines on which synapses with the parallel fibers from the granule cells normally occur. Staggerer mutant mice have been used as a source of an agranulate cerebellum in a number of investigations of the composition and function of granule cells. Kopmels et al. have reported a hyperproduction of IL1 biological activity and mRNA from LPS stimulated spleen cells of Rora^sg/Rora^sg mice on the C57BL/6J background relative to wild type siblings. In addition, homozygous mice exhibit an enhanced susceptibility to LPS-induced lung inflammation, suggesting a role for Rora in LPS-induced inflammatory responses (Stapleton CM, et al., 2005).

Strain Development
The first Rora^sg/Rora^sg mouse was observed in 1955 among the F2 progeny of a (BALB/cHm x C3H/HeJ)F1 female and a male of an obese(Lep^ob) stock of mixed background. The mutation was maintained for several generations by an intercross-backcross (within the same or a parallel lineage) mating scheme, then was backcrossed onto C57BL/6J for four generations. A Rora^sg/+ male from the fourth backcross was mated to a female C57BL/10-Myo5a^d Bmp5^se mouse to introduce the dilute and short-ear mutations into the stock in repulsion with Rora^{6 sg} ; this allowed the heterozygotes (Rora^sg + +/+ Myo5a^d Bmp5^se to be identified by a lack of either recessive phenotype. Brother-sister inbreeding was continued. At F55, Myo5a^d Bmp^se was backcrossed onto C57BL/6J seven times; at F58, Rora^sg was backcrossed onto C57BL/6J four times. The Rora^sg + +/+ Myo5a^d Bmp5^se stock was then reconstructed by crossing mice of the two independent stocks and maintained by brother-sister inbreeding. In early 1997, Myo5a^d and Bmp5^se were bred out of the stock by selective breeding assisted by PCR testing. Based on the alleles carried by this strain for 16 SSLPs mapping within 1 cM of Rora, it appears that the mutation occurred on a C3H chromosome (Hamilton et al. 1996).

Mammalian Phenotype Terms assigned by genotype The following phenotype information may relate to a genetic background differing from this JAX® Mice strain. Rorasg/Rorasg         involves: obese stock lethality-postnatal postnatal lethality (MGI Ref ID J:13140) about 50% of mutants die by weaning nervous system phenotype abnormal brain morphology (MGI Ref ID J:13140) abnormal cerebellum morphology (MGI Ref ID J:13140) cerebellum of adults shows tiny folia with indistinct fissures cerebellum is less than one-third the size of wild type littermates abnormal cerebellar foliation (MGI Ref ID J:13140) abnormal cerebellar granule layer (MGI Ref ID J:13140) granular cell layer displays a paucity of cells in mutants abnormal cerebellar molecular layer (MGI Ref ID J:13140) thin cerebellar molecular layer (MGI Ref ID J:13140) small cerebellum (MGI Ref ID J:13140) behavior/neurological phenotype abnormal motor capabilities/coordination/movement (MGI Ref ID J:13140) abnormal gait (MGI Ref ID J:13140) gait is shuffling and hesitant, interrupted every few steps by lurching motions side-to-side abnormal gait is apparent at ~2 weeks of age abnormal grip strength (MGI Ref ID J:46854) mice have a mean hanging time of 12 seconds compared to over 3 minutes for WT mice abnormal limb posture (MGI Ref ID J:13140) some animals have hindlimbs held abducted and everted at 45 degrees at rest ataxia (MGI Ref ID J:13140) clearly visible in all mice mice stumble at a rate 40 times greater than WT mice hypoactivity (MGI Ref ID J:13140) mutants remain stationary much more than littermates impaired coordination (MGI Ref ID J:13140) mice fall off an elevated rod on average of 13 seconds compared to over 3 minutes for WT mice limb grasping (MGI Ref ID J:46854) is observed in all mice tremors (MGI Ref ID J:13140) mild tremors accompany initiation of movement abnormal motor learning (MGI Ref ID J:46854) mice have an impaired ability to learn how to hang onto a rotating rod mice hang onto the rod as opposed the walking strategy WT mice exclusively use scores do not improve with 10 days of training growth/size phenotype decreased body size (MGI Ref ID J:13140) mutants are smaller than littermates Rorasg/Rorasg         involves: C57BL/6 homeostasis/metabolism phenotype abnormal lipid homeostasis (MGI Ref ID J:52105) plasma APOA1 and APOA2 concentrations are approximately 2 fold lower than in wild type controls on a normal diet, and the Apoa1 mRNA level in intestine is diminished relative to wild type, although liver expression of Apoa1 is comparable with wild type the production rate of APOA1 is diminished, but the fractional catabolic rate is comparable to wild type decreased circulating cholesterol level (MGI Ref ID J:52105) plasma total cholesterol levels are significantly lower in both male and female homozygotes than in wild type controls although cholesterol levels increase on an atherosclerotic diet, homozygotes still have lower plasma cholesterol than wild type controls also fed this diet decreased circulating HDL cholesterol level (MGI Ref ID J:52105) plasma HDL cholesterol level is significantly lower in both male and female homozygotes than in wild type controls, and females have significantly lower plasma HDL level than males both for the homozygous and wild type data sets. This is true even on an atherogenic diet. cardiovascular system phenotype atherosclerotic lesions (MGI Ref ID J:52105) the atherosclerotic lesions induced in homozygotes by 9 weeks of an atherosclerotic diet have a 6 fold greater area in female homozygotes and a 7.5 fold greater area in male homozygotes than those in wild type controls on the same diet increased susceptibility to atherosclerosis (MGI Ref ID J:52105) Although homozygotes fed a normal diet do not display abnormal atherosclerotic lesions, 9 weeks of an atherosclerotic diet induces exaggerated altherosclerotic lesions compared with wild type controls on the atherosclerotic diet immune system phenotype *normal* immune system phenotype (MGI Ref ID J:52105) white blood cell, lymphocyte, and neutrophil counts are not significantly different between homozygotes and wild type controls

Gene & Allele Details

Allele Symbol		Rorasg
Allele Name		staggerer
Common Name(s)		RORalpha-; sg;
Strain of Origin		obese stock
Gene Symbol and Name		Rora, RAR-related orphan receptor alpha
Chromosome		9
Gene Common Name(s)		9530021D13Rik; MGC119326; MGC119329; NR1F1; RIKEN cDNA 9530021D13 gene; ROR1; ROR2; ROR3; RZR-ALPHA; RZRA; neuroscience mutagenesis facility, 267; nmf267; sg; staggerer;
General Note		Homozygotes for the staggerer mutation show a staggering gait, mild tremor, hypotonia, and small size (J:13140). The cerebellar cortex is grossly underdeveloped with a deficiency of granule cells and Purkinje cells. The deficiency of granule cells in theexternal granular layer is already evident at birth. The remaining granule cells migrate inward from the external layer prematurely and then degenerate (J:5304). Purkinje cells are much delayed in postnatal differentiation and lack the dendritic spines on which synapses with the parallel fibers from the granule cells normally occur (J:5968). Golgi cells are not clearly distinguishable from Purkinje cells and it is possible that their number is also reduced (J:6185). Examination of the cerebellum of chimeras of Rorasg/Rorasg with wild-type using cellular markers for Purkinje cells and granule cells has shown that the Rorasg effect is intrinsic to the Purkinje cells and that granule cells are affected secondarily (J:28093, J:11945). Purkinje cells are probably defective as early as postnatal day 4 (J:6875). The granule cell deficiency may result from failure of Purkinje cells to adequately stimulate granule cell genesis (J:28092), as well as from later cell death due to failure of synapsis with Purkinje cells. Staggerer mice have been used as a source of an agranulate cerebellum in a number of investigations of the composition and function of granule cells.Other effects of Rorasg include persistence of multipleinnervation of Purkinje cells by climbing fibers (J:6260), reduction in size of deep cerebellar nuclei (J:6554) and inferior olivary complex (J:7948), and abnormal patterns of ganglioside composition and enzymatic activity (J:7910). Inferior olivary neuron numbers and definition of the olivary subnuclei are normal at birth but decline thereafter (J:20982). Death of inferior olivary neurons, like that of granule cells, is apparently an indirect effect of the Rorasg gene, caused by the lack of Purkinje cells with which to synapse (J:28468).Cerebellar cells of Rorasg/Rorasg mice at 7 days postnatal have immature cell surface components of a type which are present in +/+ cells at late prenatal and neonatal stages (J:6068, J:6088). In particular, the conversion of neural cell adhesion molecules (NCAM) from embryonic to adult form which is normally complete by 21 days does not occur in Rorasg/Rorasg mice (J:6930).Purkinje cells are the predominant siteof expression of calmodulin in the cerebellum of normal mice, but Rorasg/Rorasg mice do not produce any mRNA for the Calm1 locus in these cells (J:28469).Peripheral macrophages of staggerer mice, and those of several other cerebellar mutant mice, show greatly increased production of interleukin 1 beta (J:28095). Since Il1a and Tnf are also hyperexpressed in staggerer macrophages, the increases represent a general condition of hyperexcitability of these cells (J:1431). Il6 hyperexpression was also found in Rorasg/Rorasg mice but not in Grid2/+ animals (J:11652), although the latter did show hyperexpression of Il1a, Il1b, and Tnf (J:2228). Matsui et al. (J:28478) report elevated levels of somatostatin in brainsof several ataxic mouse mutants, including Rorasg homozygotes. The concentration of thyrotropin releasing hormone (TH) is also elevated in brains of these mutants (J:28467), and administration of a TRH analog, YM-14673, ameliorated the ataxia,suggesting that excess TRH may have an ataxic effect (J:18435).The reproductive life of Rorasg/Rorasg female mice is curtailed by late sexual maturation, irregular estrous cycling, and a shortened post-puberal period of reproduction (J:1960). Neonatal vestibular stimulation by rotation on a tilted plain improved gait and body balance in Rorasg/Rorasg mice and also led to improved mating efficiency (J:14535), suggesting that mating defects in these mice may bea secondary effect of the gait and balance difficulties. Long-term selection for ability to reproduce improved the maternal behavior of homozygous staggerer females without abolishing gait and balance difficulties, suggesting that Rorasg effects on reproduction are not entirely due to these difficulties (J:28416).Male staggerer mice are able to differentiate between pheromones secreted by estrous and anestrous females (J:15645). Some male Rorasg/Rorasg mice suffer from a penile disability, the penis in erection being directed rearward. The disability is intermittent even in those males subject to it, and is of little importance in determining male mating deficiency (J:32193).Although Rorasg/+ heterozygotes are behaviorally normal with normal cerebellar cytoarchitecture and composition, these heterozygotes suffer accelerated loss of Purkinje cells, granule cells, and inferior olivary neurons with age (J:1431).Rorasg/Rorasg homozygotesusually die during the fourth week of life. Some survive to adulthood, and one male has bred (J:13140).
Molecular Note		This allele contains a 6.5kb genomic deletion of an exon encoding part of the ligand binding domain. The deletion results in an exon-skipping event that introduces a shift in the reading frame. The resulting protein is predicted to be truncated due to introduction of a premature stop codon. [MGI Ref ID J:31470]

Control Information

Allele	Control
Rorasg	Typed heterozygote from the colony
Rorasg	Wild-type from the colony
		Wild type mice from the colony are the preferred controls. Untyped mice from the colony may be used; however, heterozygotes exhibit "accelerated loss of Purkinje cells, granule cells, and inferior olivary neurons with age" (MLC; Zanjani et al.1992; Hadj-Sahraoui et al.1997).
Considerations for Choosing Controls

Genotyping Protocols

Rora^sg

Colony Maintenance

Breeding & Husbandry

Rorasg/Rorasgmice can be identified by 10-15 days of age by their poor locomotor coordination, lurching movements and frequent falls; homozygotes as young as three days can be distinguished by behavioral testing (Heuze et al.1997). Homozygotes die between two to three weeks of age. Due to their early and high mortality, homozygous mutant mice are not available from our colony. In some cases, the homozygote lifespan can be extended by adding crushed grain to the bottom of the cage and keeping pups with a lactating female. As heterozygotes are indistinguishable phenotypically from wild type mice, they must be identified by a PCR based genotyping assay.

Diet Information

LabDiet® 5K52/5K67

Related Strains

Strains carrying   Rora^sg allele

000285	B6.Cg-Rorasg + +/+ Myo5ad Bmp5se/J
000237	B6C3Fe a/a-Rorasg/J

View Strains carrying   Rora^sg     (2 strains)

Strains carrying other alleles of Rora

005047

C57BL/6J-Rorasg-3J/J

View Strains carrying other alleles of Rora     (1 strain)

Additional Web Information

Congenic Nomenclature

Animal Health Reports

Room Number           FGB29

Research Applications

This mouse can be used to support research in many areas including:

Rora^sg related

Neurobiology Research
Ataxia (Movement) Defects
Cerebellar Defects (Purkinje cell defect)
Receptor Defects
Tremor Defects

References

Selected Reference(s)

Mamontova A; Seguret-Mace S; Esposito B; Chaniale C; Bouly M; Delhaye-Bouchaud N; Luc G; Staels B; Duverger N; Mariani J; Tedgui A. 1998. Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor RORalpha. Circulation 98(24):2738-43. [PubMed: 9851961]  [MGI Ref ID J:52105]

SIDMAN RL; LANE PW; DICKIE MM. 1962. Staggerer, a new mutation in the mouse affecting the cerebellum. Science 137:610-2. [PubMed: 13912552]  [MGI Ref ID J:13140]

Additional References

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Price and Supply Information

Strain Name:	B6.C3(Cg)-Rorasg/J
Stock Number:	002651

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Supply Details

Standard Supply	Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.
Supply Notes	Usually shipped between four and eight weeks of age. This strain is included in the Mouse Mutant Resource collection. Genomic DNA is available for this strain from the Mouse DNA Resource.
Licensing	See General Terms and Conditions below
Control Information	View Control Information in Strain Details.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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