Antagonism between genes driving differentiation to different fates has been repeatedly established; often, enforced expression of a differentiated phenotype, whether by specific misexpression of a gene, or fusion of cells with different phenotypes, also leads to repression of the previous phenotype (repression of alternative fates has been proposed to be an essential mechanism of differentiation, reviewed by Cory, 1999). The idea of competition is reinforced by dose-dependency effects, shown for example by comparison of heterozygous and homozygous mutants, heterokaryon studies, or knock-down mutations (Weintraub, 1993, McDevitt et al., 1997, reviewed by Orkin, 2000; Crittenden et al., 2002), by monoallelic expression of a gene such as Pax5 (Nutt et al., 1999), and by dosage effects of interacting bHLH proteins (Zhuang et al., 1996). These effects argue that boolean models, in which a specific master gene would be turned on, initiate transcription of cell-type specific genes, and repress all other fates, are insufficient.
Competition between cell-fate determining factors has also been documented at the molecular level, for example in the case of neurogenesis, where bHLH proteins play a major role in specifying neural subtypes (Chien et al., 1996, Brunet and Ghysen, 1999). Gowan et al. (2001) have identified a network of 3 cross-repressive bHLH proteins (although not all possible cross-repressions have been characterised). Briscoe et al. (2000) have also shown that a cross-repressive gene network reads out the Shh gradient in the neural tube. Two sets of two cross-repressing genes have been identified, with a possibility that there is a larger, totally cross-repressive network (all the possible interactions do not seem to have been assessed yet). The competition can also happen by physical interaction between the factors, rather than by cross-repression of transcription: in hematopoeisis, GATA-1, which drives erythroid and megakaryocytic differentiation (Visvader et al., 1992, Iwasaki et al., 2003, Kulessa et al., 1995), and PU-1, a transcription factor essential for the expression of myleoid-specific genes (reviewed by Zhang et al., 1996), as well as B-cell specific genes (Chen et al., 1996), suppress each other's activity by physical interaction (Rekhtman et al., 1999, Nerlov et al., 2000, Zhang et al., 1999). This seems to be a general phenomenon in hematopoiesis (Hu et al., 1997, reviewed by Enver and Greaves, 1998, Cross and Enver, 1997).
In addition to repressing other genes, cell-fate determining factors often enhance their own expression; it has been proposed that this is a common property of "master switches" (Rothenberg et al., 1999).