PAX6 mutation alters circadian rhythm and \u03b2 cell function in mice without affecting glucose tolerance

Nirav Florian Chhabra,Johannes Beckers,Martin Irmler,Daniel Gradinger,Martin Hrabě De Angelis,Eckhard Wolf,Oana Veronica Amarie,Marina Rubey,Birgit Rathkolb,Annette Feuchtinger,Moya Wu,Raffaele Teperino,Anna-Lena Amend,Gerhard K H Przemeck,Jan Rozman,Peter Huypens

doi:10.1038/s42003-020-01337-x

Abstract

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.

Highlights

The transcription factor Paired box domain 6 (PAX6) is involved in the development of the eye and pancreatic islets, besides being associated with sleep–wake cycles
The murine heterozygous small eye mutant Pax6Sey that lacks the C-terminal homeodomain is characterized by small eyes and iris hypoplasia[3], which is mirrored in human patients afflicted with aniridia due to heterozygous PAX6 mutation[7]
We demonstrate that Pax6Leca[2] mice have disorganized melanopsin positive intrinsically photosensitive retinal ganglionic cells in eye-like structures and display loss of circadian rhythm

Summary

Introduction

The transcription factor PAX6 is involved in the development of the eye and pancreatic islets, besides being associated with sleep–wake cycles. 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 Pax[6] mutation in the context of adult mammalian metabolism and circadian rhythm. 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. A point mutation (R128C) in the RED subdomain of the N-terminal paired domain described in a human patient[18], was studied in the mouse model Pax6Leca[2] with regards to brain development[19,20]. Our data suggest the interaction of various biological pathways affected by the pleiotropy of PAX6, which seem to protect Pax6Leca[2] mice from hyperglycemia in the absence of insulin increment

Methods

Results

Conclusion