Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants

Area of Science:

• Cell Biology
• Developmental Biology
• Biophysics

Background:

• Tissue segregation is traditionally attributed to specific binding preferences between different cadherin subtypes.
• Existing models rely on cell aggregation assays under suspension, which may not fully represent in vivo conditions.

Purpose of the Study:

• To investigate the roles of cadherin binding affinity and expression levels in controlling cell sorting and tissue assembly.
• To challenge the prevailing view that cadherin subtype specificity alone drives tissue segregation.

Main Methods:

• Utilized L cells engineered to express various cadherins (E-, P-, N-, R-, B-cadherin) in different combinations.
• Manipulated shear forces and cadherin expression levels to observe cell aggregation and segregation dynamics.
• Applied the Differential Adhesion Hypothesis to interpret observed cell behaviors.

Main Results:

• Coaggregation occurred under low shear, but high shear selectively inhibited it.
• Cells expressing P- vs E-cadherin initially coaggregated then segregated, with the lower cadherin expression level enveloping the higher.
• When cadherin expression levels were equalized, P- and E-cadherin expressing cells remained intermixed, indicating similar adhesion strengths.
• R- vs B-cadherin expressing cells showed incomplete segregation, suggesting weaker homophilic and heterophilic adhesion compared to E-P interactions.

Conclusions:

• Cadherin quantity and affinity jointly regulate tissue segregation and assembly.
• The relative strengths of cell-cell adhesions, determined by both cadherin levels and affinity, are critical for tissue organization.
• Findings challenge the exclusive role of cadherin subtype specificity in dictating tissue architecture.