Morphological and Functional Colonic Defects Caused by a Mutated Thyroid Hormone Receptor α

Area of Science:

• Endocrinology
• Gastroenterology
• Molecular Biology

Background:

• Mutations in thyroid hormone receptor alpha (TRα1) lead to resistance to thyroid hormone alpha (RTHα), characterized by growth retardation, anemia, and severe constipation.
• A mouse model (Thra1 mouse) expressing a dominant-negative TRα1 mutant (PV) accurately replicates RTHα symptoms, making it suitable for investigating constipation mechanisms.

Purpose of the Study:

• To elucidate the molecular and cellular basis of severe constipation in a mouse model of RTHα.
• To analyze colonic abnormalities in Thra1 mice using a combination of histological and molecular techniques.

Main Methods:

• Histopathological analysis, confocal fluorescence imaging, and transmission electron microscopy (TEM) were employed to examine colonic tissue.
• Gene expression profiling and Lucifer Yellow transfer assays were used to assess molecular changes and intercellular communication.

Main Results:

• Thra1 mice exhibited increased colonic transit time and reduced stool water content, consistent with constipation.
• Histological findings included expanded lamina propria, enlarged muscularis mucosa, increased collagen, shorter muscle fibers, wider gap junctions, fewer caveolae, and hypoplastic interstitial cells of Cajal (ICC).
• Reduced expression of smooth muscle contractility regulators and attenuated c-KIT signaling in ICC led to decreased rectal smooth muscle contractility.

Conclusions:

• TRα1 mutations disrupt rectal smooth muscle structure and function, impairing intercellular communication and contractility.
• These molecular defects provide a novel explanation for constipation in RTHα patients.
• The findings highlight TRα1's role in maintaining normal colonic smooth muscle physiology.