Characterization of estrogen-related receptor γ deficient mice

Introduction: The family of orphan nuclear receptors comprises ligand-independent intracellular or intranuclear transcription factors involved in basic physiological functions as cell metabolism, differentiation and growth. The last orphan nuclear receptor identified was the estrogen-related receptor (ERR) γ. Its role in determining morphological and phenotypical properties was examined using knockout mice.

Materials & methods: ERR-γ knock out mice were generated by insertion of a β-geo cassette in the first coding exon of the gene. Tissues from mice from embryonic stages to adulthood were histologically analysed after genotypical analysis. Additionally, morphometric analysis was employed to quantify the total and regional brain size.

Results: ERR-γ knockouts were underrepresented in the postnatal phase pointing to an increased lethality of the phenotype allowing only <1% of the mice to reach adult age. Compared to healthy adult mice there was a significant reduction in body weight (41.2%) beginning from P1 and a reduction in vertex-breech length (12.7%). Knockout mice were hypokinetic with hind-limb dystonia leading to tremorous circling body movements (waltzing) and retropulsion. On groß morphological organ examination, brain and stomach were altered. The telencephalic region of the ERR-γ knockout brain appeared to be shortened dorsally with the lamina quadrigemina protruding to a greater extend between the telencephalon and the cerebellum. Morphometric analysis revealed that the mesencephalic tegmentum of ERR-γ knockouts was significantly larger and the cerebellum smaller (normalized values to the absolute brain size of each genotype) compared to their wildtype and heterozygous littermates. The inner wall of the stomach of ERR-γ knockouts appeared thickened with protruding bulgy masses, which presented as a significant glandular hypertrophy without inflammatory infiltration.

Conclusions: These results corroborate existing data concerning the important role of ERR-γ in survival. They also support the hypothesis that the receptor plays a key role in neurogenesis and neuronal migration, leading to regional brain malformation and causing a morphological and functional disruption between the cerebellum and the basal ganglia, the two basic dystonia generators. They finally highlight the suppressive effect of ERR-γ on cell proliferation in the stomach leading to glandular hyperplasia if absent.