Cell focussing : Pattern formation by dancing cells

A compelling question in biology is how form arises in development and is inherited throughout generations. It was the conventional wisdom that the consecutive superposition of tissues, together with inductions, establishes the body plan. However, it was recently shown that cellular organoids even form spontaneously in tissue culture, suggesting an intrinsic order and a capacity of self-organisation of cells. I propose that the C. elegans embryo is suited to unravel the nature of this intrinsic order and self-organisation. The embryo is patterned by extensive migrations that are guided by cell focussing. These migrations are based on constant, independent and short-term random movements – the dance of cells – resembling Brownian motion. This dance of cells is also observed in diverse other bilateral animals and thus defines a new widespread biological phenomenon. The migratory system is highly inert. Only mutants of ced-10, an orthologue to human Rac1, other genes in the Rac signalling pathway, and tag-335, involved in the production of GDP-mannose, cause significant reductions of effective migrations but do not affect the dance of cells. Downstream of CED-10, the SCAR/WAVE complex known to facilitate actin branching is responsible for normal effective migrations. In mutants of this complex only 40 % of cells migrate more than their own radius and leave the position they have been placed at by the mitoses – however, it can be shown that this is just pure chance. This reduction of effective migration is most prominent during the 64- and 128-AB stages, where the ordering migrations guided by cell focussing are occurring in the WT. The loss of ced-10 mediated SCAR/WAVE activity is highly deleterious for pattern formation. To potentially explain the aberrant patterning, an agent-based in silico model was devised, where all cell displacements are based solely on random cell movements and the also random displacements by mitoses. This model reproduces both, the reduced effective migrations and the observed patterning defects in SCAR/WAVE mutants. The guidance of migrations is, thus, independently regulated from the dance itself. SAX-3/ROBO was established as a cell focussing receptor potentially regulating lateral movements. I propose a new principle of pattern formation based on the cell focussing model. The embryo is patterned by translating a random dance of cells into directed effective migrations via RAC signalling to the SCAR/WAVE complex.