Zebrafish pdx1 morphant displays defects in pancreas development and digestive organ chirality, and potentially identifies a multipotent pancreas progenitor cell

摘要

The divergent homeodomain gene pdx1 plays an essential role in vertebrate pancreas development. Loss of pdx1 function in rodents and humans perturbs growth and differentiation of the pancreas primordium and results in pancreatic agenesis Oonsson et aL, 1994; Offield et aL, 1996; Stoffers et aL, 1997). pdx1 is not required during the early stages of pancreas development as specification of the prepancreatic gut endoderm is normal in pdx1 mutants (Offield et al., 1996; Ahlgren et aL, 1996). The pancreatic bud develops a primitive ductular architecture in the absence of pdx1 gene function (Offield et al., 1996; Ahlgren et al., 1996), although subsequent endocrine and exocrine development is severely impaired. As a result, pdx1 mutants lack functional pancreatic tissue Oonsson et al., 1994; Offield et aL, 1996), and it has been suggested that pdx1 regulates pancreatic stem cell function. Consistent with this hypothesis, pdx1 expression is markedly increased in proliferating ductular cells during pancreatic regeneration (Kritzik et al., 1999; Sharma et al., 1999). Although essential for early pancreas development, pdx1 is not sufficient for pancreatic organogenesis (Grapin-Botton et al., 2001; Heller et al., 1998). When expressed ectopically, pdx1 rarely induces #beta#-cell gene expression (Ferber et al., 2000). There are, however, considerable data showing that pdx1 regulates endogenous #beta#-cell function during development, and in adults, through its transcriptional activation of genes such as insulin and glut-2 (Peshavaria and Stein, 1997; Peshavaria et al., 2000). Consistent with this role, reduced pdx1 activity is associated with diabetes in animal models and humans (Stoffers et al., 1997; Ahlgren et al., 1998; Habener and Stoffers, 1998; Peshavaria et al., 2000).