The Reg family member INGAP is a marker of endocrine patterning in the embryonic pancreas.
ABSTRACT Adult islet neogenesis is believed to recapitulate elements of pancreatic endocrine development. Identifying factors that regulate islet neogenesis-associated protein (INGAP) gene activity could provide links to pancreas development.
Predicted transcriptional regulators of INGAP were screened in an INGAP-promoter-reporter assay. Based upon their temporal expression, the occurrence of INGAP-positive cells during pancreas embryonic development were studied.
Pancreatic transcription factors, PDX-1, Ngn3, NeuroD, and Isl-1, activated the INGAP promoter, but PAX4, PAX6, and Nkx2.2 did not. The INGAP-positive cells were present in the developing pancreatic bud of the mouse embryo. Emerging clusters of unorganized endocrine cells were INGAP positive. These cells coexpressed insulin or somatostatin, but glucagon-expressing cells remained distinct. The INGAP-positive cells were also detected in the maturing neonatal endocrine cells organized into islets. In direct contrast to the embryo, glucagon localized with most INGAP-positive cells in the postnatal endocrine cells. The INGAP-positive cells juxtaposed pancreatic duct cells. A subset of 5-bromo-2'-deoxyuridine-positive/INGAP-positive cells was detected in the neonatal pancreas.
These data implicate INGAP and/or Reg family proteins in endocrine cell patterning during embryonic development and suggest that INGAP immunoreactivity is a key marker associated with early endocrine cells.
- SourceAvailable from: Sarah TerseyJournal of Diabetes Mellitus 01/2012; 02(02). DOI:10.4236/jdm.2012.22040
- [Show abstract] [Hide abstract]
ABSTRACT: We have studied the structural and dynamical properties of the biologically active pentadecapeptide of the islet neogenesis associated protein (INGAP-PP) and of two other pentadecapeptides with the same amino acid composition but randomly scrambled primary sequences, using molecular dynamic simulations. Our data demonstrates that whilst the peptides with scrambled sequences show no definite prevalent structure in solution, INGAP-PP maintains a notably stable tertiary fold, namely, a conformer with a central beta-sheet and closed C-terminal. Such structure resembles the one corresponding to the amino acid sequence of human pancreatitis associated protein-1 (PAP-1), which presents 85% sequence homology with INGAP. These results could reasonably explain why the two scrambled sequences tested showed no biological activity, while INGAP-PP significantly increases beta-cells function and mass both in vitro and in vivo conditions. The capability of INGAP-PP to temporarily adopt other closely related conformations offers also a plausible explanation for the 50 fold experimental difference in potency between the active pentadecapeptide and the whole protein. They also suggest that the C-terminal region of INGAP-PP may plausibly be the locus for its interaction with the cell receptor. Consequently, the knowledge gathered through our data can help to obtain more potent INGAP-PP analogs, suitable for the prevention and treatment of diabetes.Journal of Molecular Graphics and Modelling 12/2008; 27(6):701-5. DOI:10.1016/j.jmgm.2008.11.001 · 2.02 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: BackgroundWe previously demonstrated that somatostatin receptor type 5 (SSTR5) gene ablation results in alterations in insulin secretion and glucose metabolism, accompanied by morphologic alterations in the islets of Langerhans. The underlying mechanism(s) by which SSTR5 exerts its cellular functions remain(s) unknown. We hypothesized that SSTR5 mediates the inhibitory effect of somatostatin (SST) on insulin secretion and islet proliferation by regulating a specific set of pancreatic genes. MethodsTo identify SSTR5-regulated pancreatic genes, gene expression microarray analysis was performed on the whole pancreas of 1- and 3-month-old wild-type (WT) and SSTR5 knockout (SSTR5 −/−) male mice. Real-time RT-PCR and immunofluorescence were performed to validate selected differentially expressed genes. ResultsA set of 143 probes were identified to be differentially expressed in the pancreas of 1-month-old SSTR5 −/− mice, 72 of which were downregulated and 71 upregulated. At 3months of age, SSTR5 gene ablation resulted in downregulation of a set of 30 probes and upregulation of a set of 37 probes. Among these differentially expressed genes, there were 15 and 5 genes that were upregulated and downregulated, respectively, in mice at both 1 and 3months of age. Three genes, PAP/INGAP, ANG, and TDE1, were selected to be validated by real-time RT-PCR and immunofluorescence. ConclusionsA specific set of genes linked to a wide range of cellular functions such as islet proliferation, apoptosis, angiogenesis, and tumorigenesis were either upregulated or downregulated in SSTR5-deficient male mice compared with their expression in wild-type mice. Therefore, these genes are potential SSTR5-regulated genes during normal pancreatic development and functional maintenance.World Journal of Surgery 04/2009; 33(4):630-637. DOI:10.1007/s00268-008-9893-1 · 2.35 Impact Factor