Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas.
OBJECTIVE
The generation of mature cell types during pancreatic development depends on the expression of many regulatory and signaling proteins. In this study, we tested the hypothesis that the transcriptional regulator Islet-1 (Isl-1), whose expression is first detected in the mesenchyme and epithelium of the developing pancreas and is later restricted to mature islet cells, is involved in the terminal differentiation of islet cells and maintenance of islet mass.


METHODS
To investigate the role of Isl-1 in the pancreatic epithelium during the secondary transition, Isl-1 was conditionally and specifically deleted from embryonic day 13.5 onward using Cre/LoxP technology.


RESULTS
Isl-1-deficient endocrine precursors failed to mature into functional islet cells. The postnatal expansion of endocrine cell mass was impaired, and consequently Isl-1 deficient mice were diabetic. In addition, MafA, a potent regulator of the Insulin gene and beta-cell function, was identified as a direct transcriptional target of Isl-1.


CONCLUSIONS
These results demonstrate the requirement for Isl-1 in the maturation, proliferation, and survival of the second wave of hormone-producing islet cells.
Du
Aiping
A
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Hunter
Chad S
CS
Murray
Johanna
J
Noble
Daniel
D
Cai
Chen-Leng
CL
Evans
Sylvia M
SM
Stein
Roland
R
May
Catherine Lee
CL
D000818:Animals; D021461:Animals, Outbred Strains; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology / Q000502:physiology; D060850:LIM-Homeodomain Proteins; D051473:Maf Transcription Factors, Large / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors
D005136:Eye Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D060850:LIM-Homeodomain Proteins; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; C084010:pancreatic and duodenal homeobox 1 protein; C045073:Cre recombinase; D019426:Integrases