Identification and action of N-myc downstream regulated gene 4 A2 in rat pancreas

Pancreatic islets and acinar tissue develop from duct epithelium and share expression of several transcription factors and other molecular markers also involved with the development of neural tissues. We examined rat pancreatic tissue from fetal life until adulthood for the expression of N-myc downstream regulated gene 4 (Ndrg4), a gene shown to be expressed during neuronal cell differentiation. Isolated pancreatic ducts from neonatal rats were maintained in culture and gave rise to clusters of cells expressing nestin (NES) and PDX-1, which subsequently contained immunoreactive glucagon. Using reverse transcription PCR (RT-PCR), we identified mRNA expression and immunoreactive protein presence for NDRG4 in cultured duct-derived cells, and brain of neonatal rats. By PCR cloning of the ductal cell-derived DNA the molecular form of NDRG4 expressed in pancreatic ducts and ARIP rat pancreatic cells was identified as NDRG4A2, and its presence in intact pancreas of fetal and neonatal rats was demonstrated by immunohistochemistry. Incubation of ARIP cells with glucagon-like polypeptide-1 (GLP-1), increased the expression of NDRG4A2 and PDX-1, while decreasing DNA synthesis and promoting the appearance of glucagon-positive cells. This inhibitory effect of GLP-1 on DNA synthesis and the stimulatory effect on endocrine differentiation were reversed when the translation of NDRG4A2 was prevented using siRNA. These findings indicate that NDRG4A2 is expressed in pancreatic duct cells under GLP-1 control and may be related to a reduction in proliferation and the onset of the pancreas cell differentiation.