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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
The Retinoid-related orphan receptor beta (RORβ) gene encodes a developmental transcription factor and has 2 predominant isoforms created through alternative first exon usage; one specific to the retina and another present more broadly in the central nervous system, particularly regions involved in...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411600/ https://www.ncbi.nlm.nih.gov/pubmed/37300435 http://dx.doi.org/10.1093/g3journal/jkad131 |
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author | Murray, George C Bubier, Jason A Zinder, Oraya J Harris, Belinda Clark, James Christopher, Mia-Cara Hanley, Courtany Tjong, Harianto Li, Meihong Ngan, Chew Yee Reinholdt, Laura Burgess, Robert W Tadenev, Abigail L D |
author_facet | Murray, George C Bubier, Jason A Zinder, Oraya J Harris, Belinda Clark, James Christopher, Mia-Cara Hanley, Courtany Tjong, Harianto Li, Meihong Ngan, Chew Yee Reinholdt, Laura Burgess, Robert W Tadenev, Abigail L D |
author_sort | Murray, George C |
collection | PubMed |
description | The Retinoid-related orphan receptor beta (RORβ) gene encodes a developmental transcription factor and has 2 predominant isoforms created through alternative first exon usage; one specific to the retina and another present more broadly in the central nervous system, particularly regions involved in sensory processing. RORβ belongs to the nuclear receptor family and plays important roles in cell fate specification in the retina and cortical layer formation. In mice, loss of RORβ 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 RORβ-deficient mice. RORβ 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 RORβ variants confer susceptibility to these neurodevelopmental disorders are unknown but may involve aberrant neural circuit formation and hyperexcitability during development. Here we report an allelic series in 5 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 5 mutants reveal a shared over-representation of the unfolded protein response and pathways related to endoplasmic reticulum stress, suggesting a possible mechanism of susceptibility relevant to patients. |
format | Online Article Text |
id | pubmed-10411600 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-104116002023-08-10 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 Murray, George C Bubier, Jason A Zinder, Oraya J Harris, Belinda Clark, James Christopher, Mia-Cara Hanley, Courtany Tjong, Harianto Li, Meihong Ngan, Chew Yee Reinholdt, Laura Burgess, Robert W Tadenev, Abigail L D G3 (Bethesda) Neurogenetics The Retinoid-related orphan receptor beta (RORβ) gene encodes a developmental transcription factor and has 2 predominant isoforms created through alternative first exon usage; one specific to the retina and another present more broadly in the central nervous system, particularly regions involved in sensory processing. RORβ belongs to the nuclear receptor family and plays important roles in cell fate specification in the retina and cortical layer formation. In mice, loss of RORβ 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 RORβ-deficient mice. RORβ 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 RORβ variants confer susceptibility to these neurodevelopmental disorders are unknown but may involve aberrant neural circuit formation and hyperexcitability during development. Here we report an allelic series in 5 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 5 mutants reveal a shared over-representation of the unfolded protein response and pathways related to endoplasmic reticulum stress, suggesting a possible mechanism of susceptibility relevant to patients. Oxford University Press 2023-06-10 /pmc/articles/PMC10411600/ /pubmed/37300435 http://dx.doi.org/10.1093/g3journal/jkad131 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Neurogenetics Murray, George C Bubier, Jason A Zinder, Oraya J Harris, Belinda Clark, James Christopher, Mia-Cara Hanley, Courtany Tjong, Harianto Li, Meihong Ngan, Chew Yee Reinholdt, Laura Burgess, Robert W Tadenev, Abigail L D 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Neurogenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411600/ https://www.ncbi.nlm.nih.gov/pubmed/37300435 http://dx.doi.org/10.1093/g3journal/jkad131 |
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