Zebrafish mnx genes in endocrine and exocrine pancreas formation.

The pancreas consists of two components, which exert distinct homeostatic function, an endocrine part that secretes hormones including insulin and an exocrine part that produces digestive enzymes. In mouse, one of the factors essential for development of the pancreas is the Mnx-class homeobox transcription factor Hb9. Genetic studies showed that Hb9 is required for both initial morphogenesis of the pancreas as well as subsequent differentiation of insulin-producing beta-cells [Nat. Genet. 23 (1999) 71; Nat. Genet. 23 (1999) 67]. To get a better understanding of what role mnx genes play in pancreas development, we isolated and characterized mnx genes in the model organism zebrafish. We found one gene with homology to hb9 orthologs and two that display homology to the related chicken mnr2. Embryonic expression of the zebrafish mnx genes is very dynamic and is detected in derivatives of all three germ layers. Endodermal expression of hb9 takes place in the early gut endoderm and, later, in the endocrine pancreas and the swim bladder. In addition, one of the mnr2 genes, mnr2a, shows expression in an endodermal cell population that is initially intermingled with insulin-positive cells and that later becomes restricted to the exocrine pancreas. In knockdown studies using antisense morpholinos, we show that hb9 is essential for differentiation of the insulin-producing beta-cells but unlike mouse Hb9 is not needed for early morphogenesis of the pancreas. In contrast, mnr2a is required during late morphogenesis of the exocrine pancreas. In summary, our data suggest a tissue-specific mnx-expression code in the zebrafish pancreas and they reveal a novel role of an mnr2-related gene.