RhoA Mediates Epithelial Cell Shape Changes via Mechanosensitive Endocytosis

Area of Science:

• Cell Biology
• Developmental Biology
• Biophysics

Background:

• Epithelial remodeling involves ratcheting, where periodic contractility causes cell-cell contact length changes that stabilize into lasting morphogenetic alterations.
• Pulsatile RhoA activity is implicated in these morphogenetic ratchets, but its precise role in transient junction length changes and irreversible deformation remains unclear.

Purpose of the Study:

• To investigate how pulsatile RhoA activity regulates transient and irreversible changes in epithelial cell-cell junction length.
• To elucidate the mechanisms underlying the rectification of transient contractions into stable morphogenetic changes.

Main Methods:

• Utilized optogenetics to control pulsatile RhoA activity in a model epithelium.
• Employed an enhanced vertex model to simulate and analyze junction remodeling dynamics.
• Investigated the roles of formin-mediated E-cadherin clustering and dynamin-dependent endocytosis.

Main Results:

• Short RhoA pulses induced reversible junction contractions, while longer pulses led to irreversible changes that saturated with duration.
• A computational model demonstrated that thresholded tension remodeling and continuous strain relaxation explain these observations.
• Structuring RhoA into multiple pulses was predicted to overcome contractility saturation and was experimentally confirmed.
• Junction remodeling was found to require formin-mediated E-cadherin clustering and dynamin-dependent endocytosis.

Conclusions:

• Irreversible epithelial junction deformations are regulated by a combination of RhoA-mediated contractility, membrane trafficking, and adhesion receptor remodeling.
• The study clarifies the role of pulsatile RhoA in epithelial morphogenesis, highlighting the interplay between signaling, mechanics, and adhesion.
• Optogenetics and computational modeling provide powerful tools for dissecting complex cellular processes like epithelial remodeling.