Murine colonic mucosa hyperproliferation. I. Elevated CFTR expression and enhanced cAMP-dependent Cl(-) secretion

Area of Science:

• Gastroenterology
• Molecular Biology
• Cell Biology

Background:

• Fluid transport in the large intestine is regulated by the cystic fibrosis transmembrane conductance regulator (CFTR).
• In vitro studies show a correlation between CFTR apical membrane insertion and cAMP-mediated Cl(-) secretion in differentiated colonocytes, but this is unresolved in native tissues.
• Proliferating colonocytes may exhibit altered CFTR localization and function.

Purpose of the Study:

• To investigate the relationship between colonocyte proliferation, CFTR expression, and function in a murine model.
• To determine how CFTR is regulated during rapid cell division in the colonic epithelium.

Main Methods:

• Utilized a transmissible murine colonic hyperplasia (TMCH) model.
• Quantified CFTR mRNA and protein expression using molecular assays.
• Assessed mucosal cAMP-dependent Cl(-) secretion.
• Examined CFTR localization via immunofluorescence microscopy.

Main Results:

• Colonocyte proliferation in the TMCH model correlated with increased CFTR mRNA (8.3-fold) and protein (2.4-fold) expression.
• Enhanced mucosal cAMP-dependent Cl(-) secretion (2.3-fold) was observed.
• CFTR expression shifted from the apical pole at the crypt base to include the crypt neck region in hyperproliferating cells.
• CFTR accumulated in apically oriented subcellular perinuclear compartments in hyperproliferating colonocytes.

Conclusions:

• Colonocyte proliferation influences CFTR expression levels and cellular localization.
• CFTR accumulation in intracellular compartments may limit its surface expression and thus transmucosal current.
• This novel CFTR regulation in hyperproliferating cells explains discrepancies between high CFTR levels and functional current.