Regulation of differentiation

Some proteins have been shown to have regulative effects on differentiation in many different cellular contexts, and would thus prove interesting to incorporate in models of cellular differentiation.

• Id proteins, ubiquitously expressed during development, seem to act as inhibitors of cell differentiation, by sequestering ubiquitously-expressed class A bHLH proteins, preventing class B bHLH to form A-B heterodimers, which are transcriptionally active (Ellis et al., 1990, Benezra et al., 1990, Garrell and Modolell, 1990, reviewed by Norton et al., 1998, Norton, 2000), and by preventing DNA binding (O'Toole et al., 2003); see Massari and Murre (2000) for a precise classification of HLH proteins. Twist can act in the same way (Spicer et al., 1996), or in another, more direct way, by binding to class MyoD (Hamamori et al., 1997).

• Hes1, a bHLH protein, seems in many cases to be essential in the maintenance of an undifferentiated state (Kageyama et al., 2000); its effect can be mediated either by active repression, which involves the recruitment of Groucho, or by passive repression, which involves hetero-dimerisation with other bHLH proteins.

• The PUF family of proteins represses the expression of many genes by regulating their mRNA stability (Wickens et al., 2002), and has been proposed to have the ancestral function of maintaining proliferation of stem cells; in C. elegans, sex-determination genes are regulated by PUF members.

• NF-$\kappa$B has been shown to inhibit differentiation of mesenchymal cells, by destabilisation of the transcripts of Sox9 and MyoD, two transcription factors involved in different differentiation pathways (Sitcheran et al., 2003).

All these differentiation-inhibiting proteins have a negative effect on the strength of transcription of genes which are essential in cell-fate determination. The models presented below suggest that modulation of the transcription strength of proteins involved in cell-fate determination could allow for an initial co-existence of many antagonistic factors, followed by up-regulation of one factor at the expense of others, as the transcription strength is increased.