Myt1 and Ngn3 form a feed-forward expression loop to promote endocrine islet cell differentiation

High levels of Ngn3 expression in pancreatic progenitor cells are both necessary and sufficient to initiate endocrine differentiation. While it is clear that the Notch-Hes1-mediated signals control the number of Ngn3-expressing cells in the developing pancreas, it is not known what factors control the level of Ngn3 expression in individual pancreatic cells. Here we report that Myt1b and Ngn3 form a feed-forward expression loop that regulates endocrine differentiation. Myt1b induces glucagon expression by potentiating Ngn3 transcription in pancreatic progenitors. Vice versa, Ngn3 protein production induces the expression of Myt1. Furthermore, pancreatic Myt1 expression largely, but not totally, relies on Ngn3 activity. Surprisingly, a portion of Myt1 expressing pancreatic cells express glucagon and other alpha cell markers in Ngn3 nullizygous mutant animals. These results demonstrate that Myt1b and Ngn3 positively regulate each other's expression to promote endocrine differentiation. In addition, the data uncover an unexpected Ngn3 expression-independent endocrine cell production pathway, which further bolsters the notion that the seemingly equivalent endocrine cells of each type, as judged by hormone and transcription factor expression, are heterogeneous in their origin.