Auxilin regulates intestinal stem cell proliferation through EGFR

Area of Science:

• Stem cell biology
• Molecular and Cellular Biology
• Gastrointestinal physiology

Background:

• Adult tissue homeostasis relies on resident stem cells, whose proliferation and differentiation require precise regulation.
• Maintaining a balance between stem cell proliferation and differentiation is critical to prevent uncontrolled growth or premature cell specialization.
• The precise mechanisms controlling adult stem cell proliferation remain incompletely understood.

Purpose of the Study:

• To investigate the role of auxilin (Aux) in regulating intestinal stem cell (ISC) proliferation.
• To elucidate the signaling pathways involved in Aux-mediated control of ISC proliferation.
• To understand how Aux contributes to the maintenance of midgut homeostasis.

Main Methods:

• Utilized genetic depletion of auxilin in intestinal stem cells.
• Assessed ISC proliferation rates and midgut tissue integrity.
• Investigated Epidermal Growth Factor Receptor (EGFR) signaling pathway activation, including EGFR localization and ligand expression.
• Examined the interaction between Auxilin and EGFR.
• Intervened with EGFR signaling to observe its effect on auxilin depletion-induced phenotypes.

Main Results:

• Auxilin depletion resulted in excessive ISC proliferation and disruption of midgut homeostasis.
• The observed defects were not attributed to compromised Notch signaling.
• Auxilin depletion led to a significant upregulation of EGFR signaling, characterized by EGFR accumulation at the plasma membrane and increased ligand expression under stress.
• Auxilin was found to co-localize and associate with EGFR.
• Inhibition of EGFR signaling fully rescued the proliferation and homeostasis defects caused by auxilin depletion.

Conclusions:

• Auxilin acts as a key regulator restricting intestinal stem cell proliferation, primarily through modulation of EGFR signaling.
• Auxilin safeguards EGFR activation to ensure appropriate ISC proliferation rates, thereby maintaining midgut homeostasis.
• Targeting the Auxilin-EGFR axis presents a potential strategy for addressing dysregulated stem cell proliferation in the gut.