A Novel Cell-Type Specific Circadian Reporter Mouse Reveals Self-Sustained Food Entrainable Nature in Enteric Neurons

Area of Science:

• Chronobiology
• Gastroenterology
• Genetics

Background:

• Circadian rhythms regulate physiological processes in most body cells.
• Understanding cell-type-specific clocks is crucial for dissecting complex organ functions.
• Intestinal circadian rhythms are vital, but muscularis externa cell clocks are poorly understood.

Purpose of the Study:

• To develop a cell-type-specific reporter system for measuring intestinal circadian oscillations.
• To investigate the chronoarchitecture of the muscularis externa in the intestine.
• To explore how different intestinal cell types entrain to feeding cues.

Main Methods:

• Developed a novel Cre-dependent Per2-luciferase reporter mouse.
• Utilized ex vivo gut explants from reporter mice.
• Measured bioluminescence rhythms in five major muscularis externa cell types: enteric neurons (ENs), enteric glial cells (EGCs), interstitial cells of Cajal (ICCs), smooth muscle cells (SMCs), and muscularis macrophages (MMs).
• Assessed entrainment to feeding schedules and phase shifts under restricted feeding conditions.

Main Results:

• All five studied intestinal cell types possess autonomous circadian oscillators.
• Enteric neurons in the small intestine entrain to feeding schedules faster than those in the colon.
• Enteric neurons, smooth muscle cells, and muscularis macrophages shifted phase with daytime-restricted feeding, while interstitial cells of Cajal did not.
• Demonstrated regional and cell-type-specific differences in circadian entrainment within the intestine.

Conclusions:

• The novel reporter mouse enables precise measurement of circadian rhythms in specific peripheral cell populations.
• Distinct intestinal cell types exhibit unique entrainment properties to feeding rhythms.
• Feeding rhythms induce heterogeneous phase shifts across different gut cell clocks, impacting intestinal homeostasis.