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

Area of Science:

• Genetics and Metabolism
• Neuroscience and Chronobiology

Background:

• The transcription factor PAX6 plays a crucial role in eye and pancreatic islet development, and influences sleep-wake cycles.
• A specific point mutation in the RED subdomain of PAX6 has been identified in human patients.

Purpose of the Study:

• To comprehensively study the effects of a homozygous Pax6 mutation (Leca2) in adult mice on metabolism and circadian rhythm.
• To investigate the impact of the Leca2 mutation on the RED subdomain of PAX6.

Main Methods:

• Generation and analysis of Pax6^Leca2 homozygous mutant mice.
• Assessment of retinal structure, light perception, energy metabolism, and glucose tolerance.
• Evaluation of pancreatic beta cell function and insulin secretion.
• Analysis of hepatic glucose production and gene expression related to circadian rhythm and metabolism.

Main Results:

• Pax6^Leca2 mice exhibit underdeveloped retinal structures, impairing light perception.
• Mutant mice do not show normal daily rhythms in energy metabolism.
• Despite beta cell dysfunction and reduced insulin secretion, glucose tolerance remains normal.
• Reduced hepatic glucose production, linked to altered circadian gene expression, prevents hyperglycemia.

Conclusions:

• The RED subdomain of PAX6 is critical for the functional maturation of beta cells.
• The Leca2 mutation in PAX6 affects peripheral metabolism by disrupting circadian rhythm.
• PAX6 exhibits pleiotropic effects, influencing development, metabolism, and circadian regulation.