Coordination of local and long range signaling modulates developmental patterning.

The development of multicellular organisms relies on correct patterns of cell fates to produce functional tissues in the mature organism. A commonly observed developmental pattern consists of alternating cell fates, where neighboring cells take on distinct cell fates characterized by contrasting gene and protein expression levels, and this cell fate pattern repeats over two or more cells. The patterns produced by these fate decisions are regulated by a small number of highly conserved signaling networks, some of which are mediated by long range diffusible signals and others mediated by local contact-dependent signals. However, it is not completely understood how local and long range signals associated with these networks interact to produce fate patterns that are both robust and flexible. Here we analyze mathematical models to investigate the patterning of cell fates in an array of cells, focusing on a two cell repeating pattern. Bifurcation analysis of a multicellular ODE model, where we consider the cells as discrete compartments, suggests that cells must balance sensitivity to external signals with robustness to perturbations. To focus on the patterning dynamics close to the bifurcation point, we derive a continuum PDE model that integrates local and long range signaling. For those cells with dynamics close to the bifurcation point, sensitivity to long range signals determines how far a pattern extends in space, while the number of local signaling connections determines the type of pattern produced. This investigation provides a general framework for understanding developmental patterning, and how both long range and local signals play a role in generating features observed across biology, such as species differences in nematode vulval development and insect bristle patterning, as well as medically relevant processes such as control of stem cell fate in the intestinal crypt.