It is generally accepted that the differentiated state of a given type of cell is associated with the activity of a particular set of genes, together with the total inactivity of those sets associated with the differentiation of other cell types. It is also clear that the differentiated state of dividing or nondividing cells is often extremely stable. In this article we suggest mechanisms that may account for this stability and that also attempt to explain the ordered switching on or off of genes during development. The phenotype of the organism depends on the genotype, and the genetic contribution from both parents is in almost all cases equal. Since the ultimate control of development resides in the genetic material, the actual program must be written in base sequences in the DNA. It is also clear that cytoplasmic components can have a powerful or overriding influence on genomic activity in particular cells, yet these cytoplasmic components are, of course, usually derived from the activity of genes at some earlier stage in development. A continual interaction between cytoplasmic enzymes and DNA sequences is an essential part of the model to be presented. Modification Enzymes In bacteria, enzymes exist which modify DNA by methylating adenine in the 6-position ( 1 ). These enzymes are extremely specific in their action; they modify bases at particular positions in short defined sequences of DNA, which, at least in some instances, form a palindrome. (A palindrome in DNA is an inverted duplication, with twofold rotational symmetry. The 3′ →...

https://science.sciencemag.org/content/sci/187/4173/226.full.pdf

DNA modification mechanisms and gene activity during development.

Cadherins are a family of glycoproteins involved in the Ca2+-dependent cell-cell adhesion mechanism which is detected in most kinds of tissues. Inhibition of the cadherin activity with antibodies induces dissociation of cell layers, indicating a fundamental importance of these molecules in maintaining the multicellular structure. Cadherins are divided into subclasses, including E-, N- and P-cadherins. While all subclasses are similar in molecular weight, Ca2+- and protease-sensitivity, each subclass is characterized by a unique tissue distribution pattern and immunological specificity. Analysis of amino acid sequences deduced from cDNA encoding these molecules showed that they are integral membrane proteins of 723-748 amino acids long and share common sequences; similarity in the sequences between subclasses is in a range of 50-60% when compared within a single animal species. L cells, with very little endogenous cadherin activity, transfected with the cadherin cDNA acquired high cadherin-mediated aggregating activity. Their colony morphology was altered by the ectopic expression of cadherins from the dispersed type to the compact type, providing direct evidence for a key role of cadherins in cell-cell adhesion. It has been suggested that cadherins bind cells by their homophilic interactions at the extracellular domain and are associated with actin bundles at the cytoplasmic domain. It appears that each cadherin subclass has binding specificity and this molecular family is involved in selective cell-cell adhesion. In development, the expression of each cadherin subclass is spatiotemporally regulated and associated with a variety of morphogenetic events; e.g. the termination or initiation of expression of a cadherin subclass in a given cell collective is correlated with its segregation from or connection with other cell collectives. Antibodies to cadherins were shown to perturb the morphogenesis of some embryonic organs in vitro. These observations suggest that cadherins play a crucial role in construction of tissues and the whole animal body.

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The cadherins: cell-cell adhesion molecules controlling animal morphogenesis.

The migration and differentiation of neural crest cells.

The differential adhesion hypothesis attributes sorting-out behavior of embryonic cells to differences in the strengths of their intercellular adhesions. It suggests that cells in mixed populations rearrange themselves to minimize their total adhesive free energy. The final configuration adopted is viewed as approaching a moststable or equilibrium configuration, with the less cohesive cell/population tending to envelop the more cohesive one.



The hypothesis enables two predictions to be made. First, if the final configuration adopted by a mixed cell population indeed approximates an equilibrium configuration, the same final configuration should be approached irrespective of the starting configuration. Second, comparison of the equilibrium configurations for all possible pair-combinations of a series of cell populations of different types should reveal a hierarchy of “preference” for the internal position, reflecting a hierarchy of cellular cohesiveness.



These predictions have been tested and confirmed. First, any particular pair of tissues approaches the same final configuration, irrepective of whether the cells are initially randomly intermixed or tissue fragments are laterally joined. Second, the predicted hierarchy of preference for the internal position has been found, consistent with a hierarchy of cellular cohesiveness.



An effort has been made to clarify confusions that have arisen concerning the differential adhesion hypothesis. It is particularly stressed that the hypothesis offers an explanation for cell population behavior in terms of relative strengths of cell adhesions and makes no proposals concernnig the chemistry of adhesion. However, the value of equilibrium configurations in guiding biochemical investigations of cell surface adhesives is pointed out, as is the relevance of the present observations to natural morphogenetic events.

Does differential adhesion govern self‐assembly processes in histogenesis? Equilibrium configurations and the emergence of a hierarchy among populations of embryonic cells

Stephen A. Roth

Papers

Studies on intercellular adhesive selectivity

The measurement of intercellular adhesion.