Disease relevance of Isl1

• Upon transient transfection, both Isl1-alpha and Isl1-beta accumulate in the nuclei of murine insulinoma cells [1].
• At embryonic day 15 (E15), FGFR immunoreactivity was also detected in the ganglion cell layer, as defined by immunoreactivity for islet-1 [2].
• INTRODUCTION: Islet transplantation is a therapeutic approach to prevent diabetes complications [3].
• Relative hypoglycemia and hyperinsulinemia in mice with heterozygous lipoprotein lipase (LPL) deficiency. Islet LPL regulates insulin secretion [4].
• Recently, it has been reported that islet transplantation into patients with Type 1 diabetes may achieve insulin independence for a year or longer [Shapiro et al., Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen, N Engl J Med. 343 (2000) 230-238] [5].

High impact information on Isl1

• In these embryos, expression of Isl1 and Atoh5, essential regulators of pancreatic morphogenesis and differentiation, was severely reduced [6].
• Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation [7].
• A population of interneurons that express Engrailed1 (EN1), however, also fails to differentiate in Isl1 mutant embryos [7].
• Neurons induced in explants derived from both diencephalic and telencephalic levels of the neural plate express the LIM homeodomain protein Isl-1, and these neurons possess distinct identities that match those of the ventral neurons generated in these two subdivisions of the forebrain in vivo [8].
• Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain [9].

Biological context of Isl1

• We found that Isl1-beta is a relatively more potent transcriptional activator of the insulin promoter than Isl1-alpha and that the Isl1-alpha isoform undergoes phosphorylation [1].
• Therefore, the transcriptional activity of Isl1 is potentially regulated by the alternative splicing of its mRNA and by phosphorylation [1].
• Maternal supplementation of RA rescues early dorsal pancreas development and restores endodermal Pdx 1 and mesenchymal Isl 1 expression as well as endocrine cell differentiation [10].
• Our data indicate that Isl1 is a specific marker for a subset of pacemaker cells at developmental stages examined, and suggest genetic heterogeneity within the central conduction system and coronary smooth muscle [11].
• These genetic cell-based systems should allow the direct identification of signalling pathways which guide formation, renewal and diversification of Isl1(+) cardiogenic progenitors into distinct heart cell lineages, and would complement in vitro studies in the mouse embryo during cardiac development [12].

Anatomical context of Isl1

• Additional genetic mutations that reduce or eliminate both Isl1 and Isl2 activity result in more pronounced defects in visceral motor neuron generation and erode somatic motor neuron character [13].
• We found that Ngn2 and NeuroM transcriptionally synergize with Isl1 and Lhx3 to specify motor neurons in the embryonic spinal cord and in P19 stem cells [14].
• In conclusion, cultured pancreatic islets contain nestin and Isl-1 positive mesenchymal stem cells with multipotential developmental capacity [15].
• Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets [15].
• The LIM homeodomain transcription factor Islet1 (Isl1) is expressed in both foregut endoderm and cardiogenic mesoderm and is required for earliest stages of heart development [16].

Associations of Isl1 with chemical compounds

• We do not however find any expression of the late-stage genes (Pax4, Pax6, Isl-1, and MafA) related to beta-cell development, and the cells do not secrete insulin upon the glucose challenge [17].
• 4) Islet cAMP levels paralleled insulin secretion; in the presence of IBMX, but not glucose alone, cAMP was increased 2-fold more in alpha s+ vs. control islets [18].
• BACKGROUND: Islet transplantation studies with diabetic rodents frequently use treatment with diabetogens such as alloxan or streptozotocin to render hosts hyperglycemic [19].
• Characterization of Donor Dendritic Cells and Enhancement of Dendritic Cell Efflux With cc-Chemokine Ligand 21: A Novel Strategy to Prolong Islet Allograft Survival [20].
• (6) Islet-activating protein and 3-quinuclidinyl benzilate, two inhibitors of the zona pellucida-induced acrosome reaction, prevent sperm bound to ZP3-beads from undergoing the acrosome reaction [21].

Regulatory relationships of Isl1

• In contrast, purified Shh induced Isl-1 expression in neural tube explants, suggesting that additional neural tube-derived factors are required to induce motoneuron differentiation [22].
• DM-GRASP/BEN is expressed in the spinal cord in a subset of motoneurons expressing Islet-1, and non homogeneously in the dorsal root ganglia (DRG) [23].
• RESULTS: Islet cell neogenesis was stimulated in INGAP-treated hamsters by 10 days [24].
• Isl-1 is normally expressed in the pancreas and is required for pancreas development and endocrine cell differentiation [25].

Other interactions of Isl1

• To address this, we examined how bHLH proteins Ngn2 and NeuroM controlling neurogenesis functionally converge with LIM-homeodomain (LIM-HD) factors Isl1 and Lhx3 involved in motor neuron subtype specification [14].
• 5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1alpha [26].
• First, duct cells proliferated in the perfused segment, then cells co-expressing multiple islet hormones and transcription factors such as PDX-1, Nkx2.2, Isl1, and Pax6 were observed in duct cells, and newly formed islet-like cell clusters (ICCs) containing beta cells were recognized [27].
• To investigate common heart-limb pathways in Isl1-expressing progenitors, we ablated the Type I Bmp receptor, Bmpr1a utilizing Isl1Cre/+ [28].
• In the developing brain, almost 100% of VMH cells that contain immunoreactive ERalpha also contain Isl-1 [29].

Analytical, diagnostic and therapeutic context of Isl1

• Using double-label immunocytochemistry, we examined the overlap between immunoreactive ERalpha and Isl-1 in these different hypothalamic brain regions [29].
• The increase in serum-free cocultures was accompanied by increased mRNA and protein expression of cardiac markers and of Isl1, a marker of cardiac progenitor cells [30].
• RT-PCR analysis showed that Isl-1 transcripts are widely distributed in various mouse tissues, including pancreas, brain, lung, thymus, and ovary [31].
• The possible role of Isl-1 in insulin-gene transcription was investigated using Northern blot analysis to determine whether insulin and Isl-1 gene expression are correlated in various somatic cell hybrids [31].
• CONCLUSIONS/INTERPRETATION: Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice [32].

References