Reduction of Ptf1a Gene Dosage Causes Pancreatic Hypoplasia and Diabetes in Mice

Abstract

OBJECTIVE-Most pancreatic endocrine cells derive fromPtf1a-expressing progenitor cells. In humans, nonsense mutations in Ptf1a have recently been identified as a cause of permanent neonatal diabetes associated with pancreatic agenesis. The death of Ptf1a-null mice soon after birth has not allowed further insight into the pathogenesis of the disease; it is therefore unclear how much pancreatic endocrine function is dependent on Ptf1a in mammals. This study aims to investigate gene-dosage effects of Ptf1a on pancreas development and function in mice.RESEARCH DESIGN AND METHODS-Combining hypomorphic and null alleles of Ptf1a and Cre-mediated lineage tracing, we followed the cell fate of reduced Ptf1a-expressing progenitors and analyzed pancreas development and function in mice. RESULTS-ReducedPtf1a 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 ␤-cell number was decreased, proportion of non-␤ islet cells was increased, and ␣-cells were abnormally intermingled with ␤-cells. Interestingly, Pdx1 expression was decreased in early pancreatic progenitors but elevated to normal level at the mid-to-late stages of pancreatogenesis.

Pancreas organogenesis: From bud to plexus to gland

“…The Ptf1a cbll/cbll hypomorphic mice also develop neonatal diabetes as a result of the large loss of b-cell numbers, abnormal islet organization, and consequently insufficient insulin secretion (Fukuda et al, 2008). In contrast, studies from zebrafish carrying what is interpreted as another kind of Ptf1a hypomorphic allele, akreas, were interpreted as low Ptf1a levels promote endocrine fates, while high levels suppress endocrine fate and promote acinar differentiation .…”

Sox9 and programming of liver and pancreatic progenitors

“…One hypothesis is that a similar mechanism operates in exocrine precursors, with pancreas-specific transcription factor 1a (Ptf1a) substituting for Ngn3. Ptf1a initially functions as the pancreatic-determinant gene during the fate separation of the primitive gut epithelia into the duodenum, pancreas, and bile duct lineages (38,39). In addition, Ptf1a is indispensable for acinar cell differentiation (38,40).…”

“…In addition, Ptf1a is indispensable for acinar cell differentiation (38,40). Dosage control of Ptf1a is important for both functions; Ptf1a reduction causes the fate conversion of pancreatic precursors into the duodenal and bile duct cells and decelerates proliferation and differentiation in the exocrine lineage (39). In addition, autoregulation of Ptf1a to maintain Ptf1a dosage plays a part in the final maturation of the acinar cells (41,42).…”

The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration

“…4N-P) or immunofluorescence (data not shown). It remains possible that zebrafish tm4sf4 can coordinate regulation of pdx1 and sox4b expression levels within endocrine precursors, which could affect specific islet cell fate competency (Fukuda et al, 2008;Johansson et al, 2007;Wang et al, 2010). Alternatively, as Pdx1 is also expressed in b cells and expression of sox4b in a small subset of b cells at 20 hpf has been described (Mavropoulos et al, 2005), the increase in pdx1 and sox4b expression might be secondary to the increase in b cell numbers at 24 hpf.…”