In the course of embryonic development, cells and cell groups carry out morphogenetic movements. Through these movements the germ layers arise, and from these are formed the organs and tissues. Thirty years ago, the Principal Investigator's research provided the first evidence that these cell and tissue rearrangements are guided by intercellular adhesive interactions. According to this evidence, motile cell systems progressively rearrange toward configurations in which binding energy is maximized; hence configurations of minimal interfacial free energy. Many experiments have demonstrated that the spreading of one tissue over the surface of another and the mutual segregation of intermixed embryonic cells obey the same rules that immiscible liquid phases follow in the course of mutual spreading or de-mixing. The experiments proposed here ask whether these tissue rearrangements mimic those of liquids because they experience the same kinds of interfacial forces. It is known that specific cell adhesion molecules mediate specific cell associations. The Differential Adhesion Hypothesis proposes that they achieve this through engendering particular sets of intercellular adhesive intensities, measurable as interfacial free energies (interfacial or surface tensions at cell aggregate surfaces or interfaces). It is proposed here to use cDNA transfections to generate L-cell lines expressing on their surfaces a range of amounts of the homophilic cell adhesion molecules P, E, N and R-cadherin, respectively. From each of these cell lines, cell aggregates will be produced. Using a tissue surface tensiometer, the equilibrium surface tensions (sigmas) of each of these kinds of cell aggregates will be measured. It will be determined whether L-cell aggregates uniquely expressing different cadherins can adhere, and if so, with what intensity. The mutual envelopment tendencies of pairs of these aggregates will be determined and compared with those predicted by the relative values of the measured sigmas. Whether the sigmas of cell aggregates expressing a particular cadherin are directly proportional to the number of cadherins per cell will be determined. Measurement of sigmas of L cell aggregates expressing the same numbers of different cadherins will reveal whether differences in bond energies exist between different cadherins expressed in these cells. From the sigmas, the measured number of cadherins per cell and the measured area per cell, the (apparent) free energy per cadherin-cadherin interaction and the (apparent) association constant of the cadherin-cadherin link will be calculated. The resulting insights will elucidate the physical basis for both normal embryonic cell rearrangements and for certain developmental malformations as well as for malignant invasion and metastasis.
| Duguay, Duke; Foty, Ramsey A; Steinberg, Malcolm S (2003) Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants. Dev Biol 253:309-23 |
| Forgacs, G; Foty, R A; Shafrir, Y et al. (1998) Viscoelastic properties of living embryonic tissues: a quantitative study. Biophys J 74:2227-34 |
| Foty, R A; Steinberg, M S (1997) Measurement of tumor cell cohesion and suppression of invasion by E- or P-cadherin. Cancer Res 57:5033-6 |
| Steinberg, M S; Foty, R A (1997) Intercellular adhesions as determinants of tissue assembly and malignant invasion. J Cell Physiol 173:135-9 |
