Islet-1 is Required for the Maturation, Proliferation, and Survival of the Endocrine Pancreas

Abstract

OBJECTIVEThe 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 METHODSTo 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.RESULTSIsl-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 β-cell function, was identified as a direct transcriptional target of Isl-1.CONCLUSIONSThese results demonstrate the requirement for Isl-1 in the maturation, proliferation, and survival of the second wave of hormone-producing islet cells.

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

“…In the pancreas, where ISL1 is expressed in the normal islet cells, it is known to represent a differentiation marker. [4][5][6][7][8] Thus, expression of ISL1 in pancreatic NETs most likely reflects the high differentiation status of these neoplasms. 10,11 Accordingly, it is not surprising that ISL1 is lacking or only weakly expressed in poorly differentiated pancreatic neuroendocrine carcinomas.…”

“…3 ISL1 has an important role in the embryogenesis and differentiation of the insulinproducing pancreatic beta cells within the islets of Langerhans. [4][5][6][7] Deficiency of ISL1 was associated with absence of neural tube motor neuron differentiation in mouse experiments. 8 Apart from its role in the cell line development of the endocrine pancreas, ISL1 was found to have a major role as a marker of cardiac progenitor cell lineage.…”

Pancreas organogenesis: From bud to plexus to gland

“…Isl1, apart from its initial role in pancreatic mesenchyme for dorsal pancreas induction, is also required for the proliferation and survival of post-Ngn3 endocrine cells during the secondary transition (Du et al 2009). Since Insm-1, Rfx6, and Isl1 expression are maintained in adult islet cells, determining any remaining later functions in maturing or adult islet cells awaits a temporally controlled cell-type specific knockout.…”

In-vitro generation of human adipose tissue derived insulin secreting cells: up-regulation of Pax-6, Ipf-1 and Isl-1

“…In addition, MafA (musculoaponeurotic fibrosarcoma oncogene homolog A), a potent regulator of the Insulin gene and beta-cell function, has been identified as the direct transcriptional target of Isl-1. The requirement for Isl-1 by virtue of its requirement for the formation of dorsal mesenchyme and also its function in pancreatic endodermal cells is required for maturation, proliferation and survival of the hormone-producing islet cells (Ahlgren et al 1997;Du et al 2009). …”