Figure 8

Schematic representation of transcription factor combinations guiding beta-cell differentiation. Following the loss of Nkx2.2 or Pax6, endocrine cells retain some beta-cell characteristics, such as the expression of iAPP, Pdx1 and/or PC1/3 (indicated as "β"). Rectangles describe transcription factor combinations required to maintain the embryonic beta-cell differentiation program pre- and post-insulin expression (light and dark green, respectively). Shortly after the activation of Ngn3, both Nkx2.2 and Pax4 are necessary for the expression of additional beta-cell specific TF's such as Nkx6.1 (not depicted). Concomitantly, this combination of TF's prevents the misexpression of Arx and ghrelin in committed beta-cells. In the absence of both Nkx2.2 and Arx, endocrine cells retain the same beta-cell features as noted in the absence of Nkx2.2 only, but then express ghrelin and somatostatin. Pax6 appears necessary for maintaining normal beta-cell identity at later stages of differentiation, probably shortly after insulin activation. At that stage Pax6 presumably takes over some of the functions previously exerted by Pax4, whose expression decreases.