Reduction of <i>Ptf1a</i> Gene Dosage Causes Pancreatic Hypoplasia and Diabetes in Mice

Abstract

Reduced Ptf1a dosage resulted in pancreatic hypoplasia and glucose intolerance with insufficient insulin secretion in a dosage-dependent manner. In hypomorphic mutant mice, pancreatic bud size was small and substantial proportions of pancreatic progenitors were misspecified to the common bile duct and duodenal cells. Growth with branching morphogenesis and subsequent exocrine cytodifferentiation was reduced and delayed. Total beta-cell number was decreased, proportion of non-beta islet cells was increased, and alpha-cells were abnormally intermingled with beta-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis. CONCLUSIONS-The dosage of Ptf1a is crucial for pancreas specification, growth, total beta-cell number, islet morphogenesis, and endocrine function. Some neonatal diabetes may be caused by mutation or single nucleotide polymorphisms in the Ptf1a gene that reduce gene expression levels.