Disruption of retinoid-related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice

Abstract

The orphan nuclear receptor RORβ is expressed in areas of the central nervous system which are involved in the processing of sensory information, including spinal cord, thalamus and sensory cerebellar cortices. Additionally, RORβ localizes to the three principal anatomical components of the mammalian timing system, the suprachiasmatic nuclei, the retina and the pineal gland. RORβ mRNA levels oscillate in retina and pineal gland with a circadian rhythm that persists in constant darkness. RORβ^−/− mice display a duck‐like gait, transient male incapability to sexually reproduce, and a severely disorganized retina that suffers from postnatal degeneration. Consequently, adult RORβ^−/− mice are blind, yet their circadian activity rhythm is still entrained by light–dark cycles. Interestingly, under conditions of constant darkness, RORβ^−/− mice display an extended period of free‐running rhythmicity. The overall behavioral phenotype of RORβ^−/− mice, together with the chromosomal localization of the RORβ gene, suggests a close relationship to the spontaneous mouse mutation vacillans described >40 years ago.