Differential growth triggers mechanical feedback that elevates Hippo signaling

Area of Science:

• Biophysics
• Developmental Biology
• Cell Biology

Background:

• Mechanical stress influences cell proliferation in vitro, but its role in vivo and within developing tissues is not well understood.
• Understanding how mechanical forces are modulated and perceived by cells is crucial for comprehending tissue development.

Purpose of the Study:

• To investigate the role of mechanical stress in regulating cell proliferation during in vivo tissue development.
• To elucidate the mechanism by which differential growth influences mechanical tension and subsequent growth control.
• To determine if mechanical feedback contributes to evenly distributed growth in developing organs.

Main Methods:

• Developed a theoretical model supported by computer simulations using a generalized vertex model.
• Investigated the modulation of cytoskeletal tension along cell junctions in response to differential growth.
• Analyzed the impact of reduced tension on the biomechanical Hippo pathway, including Ajuba LIM protein and Warts kinase recruitment.
• Assessed the effect on the activity of the Yorkie transcription factor.
• Utilized genetic manipulation in Drosophila wings to suppress mechanical feedback and observe effects on cell proliferation patterns.

Main Results:

• Demonstrated that differential growth reduces cytoskeletal tension along cell junctions in faster-growing cells.
• Proposed and validated a theoretical model explaining this tension reduction.
• Showed that reduced tension modulates the Hippo pathway, decreasing Ajuba LIM protein and Warts kinase recruitment, and lowering Yorkie activity.
• Confirmed that genetically suppressing mechanical feedback alters cell proliferation patterns in Drosophila wings.

Conclusions:

• Established a specific mechanism for mechanical feedback contributing to evenly distributed growth.
• Provided experimental evidence for mechanical stress induction by differential growth.
• Identified a molecular link between mechanical stress and growth regulation in developing organs.
• Confirmed and extended the mechanical feedback hypothesis in the context of organ development.