Mechanisms of cell fate specification by the ARP/ASCL factors in the zebrafish digestive system

Recently, we discovered that pancreatic endocrine cell fate in zebrafish is not controlled by Neurog3 like in mouse but by a couple of ARP/Ascl factors, Ascl1b and Neurod1. Furthermore, we identified Ascl1a as the cell fate determinant of the secretory lineage in the zebrafish intestine while this function is fulfilled by Atoh1 in the murine intestine. These data highlighted a striking diversity in the ARP/Ascl factors involved in the determination and differentiation of the endocrine cells and showed that the choice of these factors depends not only on the organ considered but also on the species. The next question was to understand this diversity and determine whether these ARP/Ascl factors are interchangeable. We first test whether expression of Atoh1 could rescue the loss of secretory cells in the gut of the pia/ascl1a mutant by using the inducible transgenic lines Tg(hsp70:atoh1a) or Tg(Hsp70:atoh1b-Myc). We found that both lines can rescue efficiently the loss of secretory cells in the gut of the pia/ascl1a mutant. Furthermore, this rescue can be also obtained using two others ARP/ASCL factors, namely neurod1 or Ascl1b, suggesting that all these ARP/Ascl factors are interchangeable. However, the phenotype of the rescued embryos is slightly different from wild type embryos as they display an excess of goblet cells and a reduced number of enteroendocrine cells and we are currently investigating the reasons of such difference. Interestingly, we also found that the overexpression of Atho1 factors leads to ectopic endocrine cells in the liver and the anterior endoderm and the characterization of these ectopic cells will give insights about the mechanism of cell specification by the ARP/ASCL factors.