Islet-1 is Required for the Maturation, Proliferation, and Survival of the Endocrine PancreasOBJECTIVE: 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. RESEARCH DESIGN AND 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.
Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell DevelopmentJingxuan Liu, Chad S. Hunter, Aiping Du et al.|Journal of Biological Chemistry|2011 Aristaless related homeodomain protein (Arx) specifies the formation of the pancreatic islet α-cell during development. This cell type produces glucagon, a major counteracting hormone to insulin in regulating glucose homeostasis in adults. However, little is known about the factors that regulate Arx transcription in the pancreas. In this study, we showed that the number of Arx+ cells was significantly reduced in the pancreata of embryos deficient for the Islet-1 (Isl-1) transcription factor, which was also supported by the reduction in Arx mRNA levels. Chromatin immunoprecipitation analysis localized Isl-1 activator binding sites within two highly conserved noncoding regulatory regions (Re) in the Arx locus, termed Re1 (+5.6 to +6.1 kb) and Re2 (+23.6 to +24 kb). Using cell line-based transfection assays, we demonstrated that a Re1- and Re2-driven reporter was selectively activated in islet α-cells, a process mediated by Isl-1 in overexpression, knockdown, and site-directed mutation experiments. Moreover, Arx mRNA levels were up-regulated in islet α-cells upon Isl-1 overexpression in vivo. Isl-1 represents the first known activator of Arx transcription in α-cells, here established to be acting through the conserved Re1 and Re2 control domains. Aristaless related homeodomain protein (Arx) specifies the formation of the pancreatic islet α-cell during development. This cell type produces glucagon, a major counteracting hormone to insulin in regulating glucose homeostasis in adults. However, little is known about the factors that regulate Arx transcription in the pancreas. In this study, we showed that the number of Arx+ cells was significantly reduced in the pancreata of embryos deficient for the Islet-1 (Isl-1) transcription factor, which was also supported by the reduction in Arx mRNA levels. Chromatin immunoprecipitation analysis localized Isl-1 activator binding sites within two highly conserved noncoding regulatory regions (Re) in the Arx locus, termed Re1 (+5.6 to +6.1 kb) and Re2 (+23.6 to +24 kb). Using cell line-based transfection assays, we demonstrated that a Re1- and Re2-driven reporter was selectively activated in islet α-cells, a process mediated by Isl-1 in overexpression, knockdown, and site-directed mutation experiments. Moreover, Arx mRNA levels were up-regulated in islet α-cells upon Isl-1 overexpression in vivo. Isl-1 represents the first known activator of Arx transcription in α-cells, here established to be acting through the conserved Re1 and Re2 control domains.
Service Users’ Perceptions About Their Hospital Admission Elicited by Service User–Researchers or by CliniciansOBJECTIVE Service users may express positive, ambivalent, or negative views of their hospital admission. The objective of this study was to determine whether the background of the interviewer-service user-researcher or clinician-influences the information elicited. The primary outcome was the level of perceived coercion on admission, and secondary outcomes were perceived pressures on admission, procedural justice, perceived necessity for admission, satisfaction with services, and willingness to consent to participate in the study. METHODS Participants voluntarily and involuntarily admitted to three hospitals in Ireland were randomly allocated to be interviewed at hospital discharge by either a service user-researcher or a clinician. Interviewers used the MacArthur Admission Experience Survey and the Client Satisfaction Questionnaire. RESULTS A total of 161 participants were interviewed. No differences by interviewer status or by admission status (involuntary or voluntary) were found in levels of perceived coercion, perceived pressures, procedural justice, perceived necessity, or satisfaction with services. Service users were more likely to decline to participate if their consent was sought by a service user-researcher (24% versus 8%, p=.003). CONCLUSIONS Most interviewees gave positive accounts of their admission regardless of interviewer status. The findings indicate that clinicians and researchers can be more confident that service users' positive accounts of admissions are not attributable to a response bias. Researchers can also feel more confident in directly comparing the results of studies undertaken by clinicians and by service user-researchers.