PAX6 mutation alters circadian rhythm and β cell function in mice without affecting glucose tolerance
| Autor: | Daniel Gradinger, Oana V. Amarie, Marina Rubey, Johannes Beckers, Jan Rozman, Anna-Lena Amend, Gerhard K. H. Przemeck, Moya Wu, Birgit Rathkolb, Raffaele Teperino, Annette Feuchtinger, Peter Huypens, Martin Hrabě de Angelis, Martin Irmler, Nirav Florian Chhabra, Eckhard Wolf |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Blood Glucose
Male Retinal Ganglion Cells 0301 basic medicine medicine.medical_specialty PAX6 Transcription Factor Physiology Mutant Medicine (miscellaneous) Context (language use) Biology medicine.disease_cause Article Retina General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Insulin-Secreting Cells Internal medicine Insulin Secretion medicine Animals Circadian rhythm lcsh:QH301-705.5 Transcription factor Mice Inbred C3H Mutation Pancreatic islets Point mutation Endocrine system and metabolic diseases Optic Nerve Mice Mutant Strains eye diseases Circadian Rhythm Glucose 030104 developmental biology Endocrinology medicine.anatomical_structure Gene Expression Regulation Liver lcsh:Biology (General) sense organs PAX6 General Agricultural and Biological Sciences 030217 neurology & neurosurgery |
| Zdroj: | Communications Biology, Vol 3, Iss 1, Pp 1-14 (2020) Comm. Biol. 3:628 (2020) Communications Biology |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-020-01337-x |
| Popis: | The transcription factor PAX6 is involved in the development of the eye and pancreatic islets, besides being associated with sleep–wake cycles. Here, we investigated a point mutation in the RED subdomain of PAX6, previously described in a human patient, to present a comprehensive study of a homozygous Pax6 mutation in the context of adult mammalian metabolism and circadian rhythm. Pax6Leca2 mice lack appropriate retinal structures for light perception and do not display normal daily rhythmic changes in energy metabolism. Despite β cell dysfunction and decreased insulin secretion, mutant mice have normal glucose tolerance. This is associated with reduced hepatic glucose production possibly due to altered circadian variation in expression of clock and metabolic genes, thereby evading hyperglycemia. Hence, our findings show that while the RED subdomain is important for β cell functional maturity, the Leca2 mutation impacts peripheral metabolism via loss of circadian rhythm, thus revealing pleiotropic effects of PAX6. Nirav Chhabra et al. characterize adult mice carrying a homozygous mutation in Pax6 that was identified in a patient with foveal hypoplasia. They find that the Pax6 point mutation has pleiotropic effects, including defects in the mouse retinal structures, loss of the optic nerve, changes in energy metabolism and circadian rhythms, and dysregulation of genes expressed in the pancreas. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|