RANK drives structured intestinal epithelial expansion during pregnancy

Area of Science:

• Reproductive biology
• Gastroenterology
• Cellular and molecular biology

Background:

• Mammalian reproduction involves significant physiological adaptations for maternal and offspring well-being.
• The intestinal epithelium's role in these adaptations, particularly during pregnancy and lactation, remains incompletely understood.

Purpose of the Study:

• To investigate the molecular mechanisms driving intestinal epithelial expansion during mammalian pregnancy and lactation.
• To identify key pathways regulating villous morphology and intestinal surface area during reproduction.

Main Methods:

• In vivo studies using mice, including genetic manipulation (Rank deficiency).
• In vitro studies using mouse and human intestinal organoids.
• Analysis of molecular signaling pathways, including Receptor activator of nuclear factor-κB (RANK) and Bone Morphogenetic Protein (BMP) signaling.

Main Results:

• The intestinal epithelium expands during pregnancy and lactation, characterized by novel villous geometry.
• The RANK-RANKL pathway is identified as a critical regulator of this expansion in mice and organoids.
• RANK-RANKL signaling protects gut epithelial cells, influences the stem cell niche via BMP signaling, and promotes villous elongation.
• Maternal deficiency in intestinal RANK leads to reduced offspring weight and glucose intolerance.
• Constitutive RANK activation causes intestinal expansion followed by villous and stem cell loss, and inhibits tumor formation.

Conclusions:

• RANK-RANKL is a key pathway driving intestinal epithelial expansion during pregnancy and lactation, a fundamental reproductive adaptation.
• This pathway is crucial for maintaining gut integrity and supporting offspring development, with implications for metabolic health.
• Understanding RANK-RANKL's role offers insights into tissue remodeling, stem cell regulation, and potential therapeutic targets.