Developmental Gene Expression in the Human Fetal Pancreas

Abstract

Differential developmental regulation of pancreasspecific genes has not been reported for the human fetal pancreas. We have therefore undertaken a systematic, quantitative analysis of the transcriptional levels of various genes in the human pancreas at different stages of fetal and postnatal development. Using sensitive ribonuclease protection assays, in situ hybridization, and the polymerase chain reaction, our results indicate the following: 1 ) Transcriptional levels of insulin and amylin remain lower in the fetal than in the adult pancreas, whereas glucagon and somatostatin mRNA levels are consistently greater after 14 wk gestation than postnatally. These results are in agreement with previous immunohistochemical studies of these gene products.2 ) The reg gene exhibits a 20-fold increase in mRNA levels after 16 wk gestation. The gene is expressed exclusively in the acinar cells and does not colocalize with insulin. This restricted exocrine expression does not indicate a direct role for the reg gene in islet development. 3 ) Glucose transporter 2 and glucokinase mRNA are detectable as early as 13 wk gestation and remain low throughout development. Glucose transporter 1 reaches adult transcriptional levels by 18 wk gestation. The early detection of glucose transporter 2 and glucokinase implies that lack of expression of these "glucose sensor" genes does not account for the known insensitivity of the fetal p-cells to glucose. (Pediafr Res 36: 537-544, 1994)

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“…From 15 to 16 weeks of gestation, increasing proportions of beta cells were labelled with K þ ATP channel antibodies and a high proportion of beta cells were labelled with GLUT1-and GCKspecific antibodies from this time. Perifusion studies with isolated human fetal islet preparations show sustained insulin secretion in response to glucose from only 17 weeks of gestation [2], an age similar to our detection of the major beta cell glucose sensors. Deficiencies in key glucosesensing components within beta cells may therefore contribute to poor insulin secretion in early fetal life.…”

“…Previous studies, using molecular and electrophysiological approaches, have established the expression of glucose transporters, GCK and functional K þ ATP channels in the human fetal pancreas from 13 weeks of gestation [2,3] and it has been generally assumed, but not formally demonstrated, that these glucose-sensing components are localised to beta cells. The experimental data presented here are consistent with the early developmental appearance of GLUT2 and K + ATP channels, but suggest that these proteins are predominantly localised to pancreatic epithelium, rather than endocrine cells, prior to 15 weeks of gestation.…”

“…mRNAs for GLUT1, GLUT2 and GCK are detected in the human fetal pancreas as early as 13 weeks of gestation [2]. ATP generated from glucose metabolism causes beta cell depolarisation through closure of ATP-sensitive K + channels (K þ ATP channels) comprising two subunits, the inward rectifying K + channel (KIR6.2, also known as KCNJ11) and the sulfonylurea receptor 1 SUR1 (also known as ABCC8).…”

Expression of Reg Family Proteins in Embryonic Stem Cells and Its Modulation by Wnt/β-Catenin Signaling

“…In a recent report [ 64 ], Reg1 was shown to promote the differentiation of pancreatic acinar cells whereas inhibition of Reg1 led to β-cell and possibly ductal cell phenotypes. The Reg1 mRNA exhibits a 20-fold increase in the acinar pancreas after 16 weeks of gestation [ 65,66 ] in human embryos. The expression of PAP genes has also been detected in fetal pancreas, stomach, jejunum, and colon [ 67 ].…”

Gene- and cell-based therapeutics for type I diabetes mellitus

“…[191][192][193] The Reg-secreted protein, in particular, promotes increases in b-cell mass in rats that had undergone pancreatectomy. [194][195][196] The expression and secretion of another molecule that belongs to the Reg family of proteins, termed islet neogenesis-associated protein (INGAP), is upregulated in hamster islets where neogenesis was artificially induced.…”