| First Author | Murray GC | Year | 2023 |
| Journal | G3 (Bethesda) | PubMed ID | 37300435 |
| Mgi Jnum | J:337403 | Mgi Id | MGI:7494095 |
| Doi | 10.1093/g3journal/jkad131 | Citation | Murray GC, et al. (2023) An allelic series of spontaneous Rorb mutant mice exhibit a gait phenotype, changes in retina morphology and behavior, and gene expression signatures associated with the unfolded protein response. G3 (Bethesda) |
| abstractText | The Retinoid-related orphan receptor beta (RORbeta) gene encodes a developmental transcription factor and has two predominant isoforms created through alternative first exon usage; one specific to retina and another present more broadly in the central nervous system, particularly regions involved in sensory processing. RORbeta belongs to the nuclear receptor family and plays important roles in cell fate specification in retina and cortical layer formation. In mice, loss of RORbeta causes disorganized retina layers, postnatal degeneration, and production of immature cone photoreceptors. Hyperflexion or "high-stepping" of rear limbs caused by reduced presynaptic inhibition by Rorb-expressing inhibitory interneurons of the spinal cord is evident in RORbeta-deficient mice. RORbeta variants in patients are associated with susceptibility to various neurodevelopmental conditions, primarily generalized epilepsies, but including intellectual disability, bipolar and autism spectrum disorders. The mechanisms by which RORbeta variants confer susceptibility to these neurodevelopmental disorders is unknown but may involve aberrant neural circuit formation and hyperexcitability during development. Here we report an allelic series in five strains of spontaneous Rorb mutant mice with a high-stepping gait phenotype. We show retinal abnormalities in a subset of these mutants and demonstrate significant differences in various behavioral phenotypes related to cognition. Gene expression analyses in all five mutants reveal shared over-representation of the unfolded protein response and pathways related to endoplasmic reticulum stress, suggesting a possible mechanism of susceptibility relevant to patients. |
