Molecular and Cellular Endocrinology 186 (2002) 1 – 5 At the Cutting Edge Age-related phenotypes in the staggerer mouse expand the ROR nuclear receptor’s role beyond the cerebellum Christopher I. Jarvis a , Bart Staels b , Bernard Brugg a , Yolande Lemaigre-Dubreuil a , Alain Tedgui c , Jean Mariani a, * a Uniersite ´ Pierre et Marie Curie and CNRS, FRE 2371 Neurobiologie des Processus Adaptatifs, 9 quai St. Bernard, 75005 Paris, France b UR545 INSERM, Institut Pasteur de Lille, 1 rue du Pr Calmette, Faculte ´ de Pharmacie, Uniersite ´ de Lille II, 59019 Lille, France c U541 INSERM, Ho ˆpital Lariboisie `re, 41 bouleard de la Chapelle, 75475 Paris, France Received 31 May 2001; accepted 5 September 2001 Abstract The homozygous mutant mouse staggerer (RORa sg /RORa sg ), was initially described as ataxic, due to the presence of massive neurodegeneration in the cerebellum [Science 136 (1962) 610]. The identification of the widely expressed Retinoic acid receptor-related Orphan Receptor, NR1F1 (ROR) gene as the site of mutation in the staggerer mouse has led to great progress in understanding the molecular basis of its phenotype in recent years [Nature 379 (1996) 736]. ROR is a transcription factor, belonging to the nuclear receptor superfamily, for which no natural ligand has yet been identified. Mice engineered for the disruption of the gene encoding ROR display the same cerebellar atrophic phenotype as the staggerer mouse [Proc. Natl. Acad. Sci. USA 95 (1998) 3960]. More recently, it has been shown that the mutation is semi-dominant, as heterozygous animals display an increased loss of Purkinje cells with age. Furthermore, a number of additional phenotypes outside the nervous system have recently been identified. These include a greater susceptibility to atherosclerosis [Circulation 15 (1998) 2738], immunodeficiencies linked to the overexpression of inflammatory cytokines [J. Neurochem. 58 (1992) 192], abnormalities in the formation and maintenance of bone tissue [Proc. Natl. Acad. Sci. USA 97 (2000) 9197] and changes in muscle differentiation [Nucleic Acids Res. 27 (1999) 411]. Thus, ROR has been directly linked to a number of age-related pathologies of great medical interest. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Purkinje cells; Osteoporosis; Atherosclerosis; NF-B; Rev-erb; CaM kinase www.elsevier.com/locate/mce 1. Introduction The initial characterisation of the staggerer mutation in the mouse described a recessive, ataxic phenotype, caused by a massive neurodegeneration in the cerebel- lum (Sidman et al., 1962; Herrup and Mullen, 1979). The identification of the ROR gene as the site of mutation in the staggerer mouse has led to great pro- gress in recent years (Hamilton et al., 1996). As ROR is expressed in a wide variety of tissues, attention has been redirected to the search for its role in age-related, degenerative pathologies away from the cerebellum. The ROR gene encodes a protein that is a member of a superfamily of nuclear receptors which includes the Peroxisome Proliferator-activated Receptors (PPARs) and the receptors for the glucocorticoids. Furthermore, mice engineered for the disruption of this transcription factor have displayed a similar cerebellar phenotype as the staggerer mouse (Steinmayr et al., 1998), demon- strating that the phenotype of the staggerer mutation is most likely caused by a complete loss of function of the ROR gene. 2. Function and activity of the ROR protein The ROR protein is composed of a series of do- mains termed, from N- to C-terminus, A through F. The first two, domains A and B, vary between the gene’s four different splice isoforms. These splice vari- * Corresponding author. Tel.: +33-1-44-27-3240; fax: +33-1-44- 27-2280. E-mail address: jean.mariani@snv.jussieu.fr (J. Mariani). 0303-7207/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(01)00668-2