Figure 8. Model of the E-box-dependent co-operation of E proteins with proneural proteins.

In neural progenitors, ID proteins (ID) physically sequester E proteins (E), thereby regulating their ability to interact with ASCL1 and ATOH1 (A) or NEUROG1/2 (N). When E protein availability is limited, ASCL1/ATOH1 cannot bind optimally to high affinity CAGSTG E-box motifs, resulting in poor regulation of their target genes and favouring symmetric proliferative (PP) divisions and hence, progenitor maintenance. The release of E proteins from IDs allows heterodimerization with ASCL1/ATOH1, resulting in optimal binding to CAGSTG motifs, correct regulation of the target genes and the appropriate increase in neurogenic asymmetric (PN) and self-consuming (NN) divisions. In the absence of E proteins, NEUROG1/2 bind to high affinity CADATG motifs, possibly as homodimers, and regulate the expression of target genes in an exacerbated manner. This deregulation results in excessive neurogenic divisions that cause premature neuronal differentiation and depletion of the progenitor pool. In the presence of E proteins and when N-E heterodimers are formed, the activity of NEUROG1/2 is moderated and the proportions of the different modes of divisions are balanced appropriately to sustain the progenitor population while promoting correct neuronal differentiation.