During embryonic development, cell-cell interaction plays a pivotal role in generating many types of cells that constitute a functional adult body. The most prevalent of such interaction is embryonic induction, a process by which part of a tissue within the embryo changes its direction of differentiation into another upon receipt of a signal emanating from the nearby tissue. Such induction events, however, are transient and therefore the cells that have received the signal must 'remember' the event until they terminally differentiate.
The precursor cells generated by an embryonic induction tend to stay together and form a cell group of like character. Despite the fact that those cells often proliferate and their surrounding environment changes as a consequence of morphogenesis, cells in such a group behave as a collective and express the same set of genes that are unique to their differentiation process. One of the mechanisms that control such collective behaviour of cells during animal development is the so-called community effect [1
]. A community effect was first discovered in the muscle precursor cells of Xenopus
]. Muscle cells are formed from mesoderm, which itself is generated by an inductive interaction of cells in the equatorial region of blastula embryos in Xenopus
. Naïve ectoderm cells from blastula embryos change their fate to mesodermal one when juxtaposed to the endodermal tissue that produces the mesoderm-inducing signalling molecules Activin and Xnr (Xenopus n
elated) proteins. Mesoderm cells that contain muscle precursor cells induced in this way or isolated from early embryos can differentiate into muscle cells when cultured as a group of many cells but not as single cells (Figure ) [3
]. This community effect of many nearby muscle precursor cells requires cell-cell interaction mediated by FGF4 (F
actor 4) protein. FGF4 (also known as embryonic FGF or eFGF in Xenopus
) is distinct from the mesoderm-inducing signals [4
]. FGF4 and the early mesodermal transcription factor Xbra (Xenopus Br
achyury) induce expression of each other, thus forming a positive feedback among a group of cells [5
]. If FGF signalling is blocked by the expression of a dominant negative form of FGF receptor, Xbra expression will be lost [7
]. Although it is intuitively apparent that cell-cell communication by diffusible factors plays a crucial role in the community effect, its mechanism is not immediately obvious. Bolouri and Davidson proposed a model of the community effect in sea urchin embryos, which is based on the gene regulatory network operating in the oral ectoderm [8
]. In their model, cell-cell communication also plays the central role for the community effect, which is mediated by the Nodal
gene product. The basic regulatory unit for a community effect thus seems to be a self-activating feedback loop of a gene that expresses extracellular signalling ligands.
Diagram depicting the community effect in development. This figure illustrates the concept of the community effect in an abstract manner. See Introduction for a description of the community effect in muscle development.
The model of Bolouri and Davidson also incorporated an interlinked loop of negative feedback by the Nodal antagonist Lefty. This negative feedback is responsible for restricting the area of Nodal expression within the boundary of the oral ectoderm [9
]. Although their model provides an underlying logic to the gene regulatory network of a community effect, many questions still remain unanswered: Is positive feedback signalling among cells sufficient for the community effect? Why does the community effect require many cells? How is such a population size determined? We have addressed these questions theoretically using a combination of stochastic and deterministic modelling methods. We found that a simple linear gene cascade that produces a diffusible factor for cell-cell communication is sufficient to reproduce the community effect in development. We derived the formula for the minimal number of cells required for a community effect and discuss its wider implications for the mechanism of collective behaviour of cells.