Figure 3

a, Schematic illustrations of three distinct modes of probabilistic differentiation (top) and corresponding time traces (below), as indicated. b, Noise in the lac system. Top, schematic view of the lac-positive feedback loop: increased expression of the LacY transporter (green cylinder) increases intracellular inducer levels (light blue circle), inhibiting the LacI repressor (dark blue) and further increasing expression. Bottom, lacY expression is blocked upon simultaneous binding of LacI to two operator sites on the lac promoter, which forms a DNA loop. Unbinding from one of these sites leads to transcription of at most one mRNA before re-looping, causing small increases in LacY. More rarely, LacI will be completely released from both sites, resulting in a large burst of mRNA and proteins that may lead to a switch of the positive feedback loop. c–f, Probabilistic differentiation in embryonic stem cells. c, Expression of Nanog (red) and Gata6 (green) in individual cells in the inner cell mass of a mouse embryo. Note the predominantly exclusive but spatially disorganized expression of the two genes. DAPI, 4',6-diamidino-2-phenylindole. Image adapted with permission from ^{ref. 59}. d, e, Two models for patterning of the inner cell mass (ICM). d, In a positional model cell, fate is determined by position through signalling from neighbouring cells. e, In the stochastic sorting model, cells first differentiate randomly, and subsequently move to appropriate positions based on their identity. f, Stem cell populations are not homogeneous but rather consist of a dynamic distribution of sub-states (dim green and red circles). Some sub-states resemble the differentiated states to which they are more prone to differentiate (bright green and red circles).