Nup358 Sustains Intestinal Epithelial Homeostasis by Preventing Dvl1 Condensate Formation to Restrain Wnt Signaling

Area of Science:

• Cell Biology
• Molecular Biology
• Gastroenterology

Background:

• Nucleoporins (Nups) perform critical tissue-specific regulatory functions beyond their structural roles in the nuclear pore complex.
• The Wnt signaling pathway is crucial for intestinal homeostasis, regulating stem cell function and epithelial development.

Purpose of the Study:

• To identify the role of nucleoporin Nup358 in regulating Wnt signaling within the intestinal epithelium.
• To elucidate the molecular mechanisms by which Nup358 controls Wnt pathway activity and intestinal integrity.

Main Methods:

• Conditional knockout mouse models to ablate Nup358 in adult mice.
• Analysis of intestinal crypt-villus architecture and cell populations (ISCs, TA progenitors).
• Biochemical assays to investigate Nup358 interactions with Dvl1 and downstream Wnt pathway components.

Main Results:

• Nup358 ablation in mice leads to severe disruption of intestinal crypt-villus architecture and epithelial integrity.
• While intestinal stem cells (ISCs) remain stable, the transit-amplifying (TA) progenitor pool is depleted.
• Nup358 inhibits Dvl1 phase separation, preventing Tankyrase-mediated Axin1 degradation and subsequent Wnt pathway hyperactivation.

Conclusions:

• Nup358 acts as a critical repressor of Wnt signaling in the intestinal epithelium.
• By dampening Wnt signaling, Nup358 safeguards intestinal homeostasis, enabling ISC differentiation and TA progenitor survival.
• Nup358 functions as a molecular safeguard preventing aberrant Wnt signal amplification in intestinal crypts.