Alternative titles; symbols
HGNC Approved Gene Symbol: ISL1
Cytogenetic location: 5q11.1 Genomic coordinates (GRCh38): 5:51,383,448-51,394,730 (from NCBI)
The ISL1 gene encodes a member of the LIM/homeodomain family of transcription factors that binds to the enhancer region of the insulin gene (176730).
Because insulin deficiency, either relative or absolute, is a cardinal feature of noninsulin-dependent diabetes mellitus (NIDDM; 125853), Tanizawa et al. (1994) investigated the possible involvement of mutations in genes that regulate insulin production. Rat Isl1 was the first insulin enhancer-binding protein to be isolated; Tanizawa et al. (1994) used the rat gene to isolate a partial human ISL1 cDNA and subsequently to isolate genomic clones. A simple sequence repeat was found in the ISL1 gene. PCR amplification of this region of genomic DNA revealed 12 alleles in St. Louis African Americans (heterozygosity = 0.87), 14 alleles in black Nigerians (heterozygosity = 0.89), 8 alleles in Japanese (heterozygosity = 0.69), and 8 alleles in Caucasians (heterozygosity = 0.81). Allelic frequencies in the gene did not differ between patients with NIDDM and nondiabetic control subjects in 2 black populations.
Tsuchida et al. (1994) found that the combinatorial expression of 4 LIM genes, Isl1, Isl2 (609481), Lim1 (LHX1; 601999), and Lim3 (LHX3; 600577), in the developing embryonic chicken defined subclasses of motor neurons that segregated into columns in the spinal cord and selected distinct axonal pathways. These genes were expressed prior to the formation of distinct motor axon pathways and before motor columns appeared.
Lee and Pfaff (2003) showed that Neurod4 (611635) and Ngn2 (NEUROG2; 606624) actively participated with Isl1 and Lhx3 to specify motor neuron subtype in embryonic chicken spinal cord and in P19 mouse stem cells.
Laugwitz et al. (2005) reported the identification of ISL1-positive cardiac progenitors in postnatal rat, mouse, and human myocardium. A cardiac mesenchymal feeder layer allows renewal of the isolated progenitor cells with maintenance of their capability to adopt a fully differentiated cardiomyocyte phenotype. Tamoxifen-inducible Cre/lox technology enabled selective marking of this progenitor cell population, including its progeny, at a defined time, and purification to relative homogeneity. Coculture studies with neonatal myocytes indicated that ISL1-positive cells represent authentic, endogenous cardiac progenitors (cardioblasts) that display highly efficient conversion to a mature cardiac phenotype with stable expression of myocytic markers (25%) in the absence of cell fusion, intact calcium cycling, and the generation of action potentials.
Mitsiadis et al. (2003) studied the expression pattern of Isl1 in developing mouse teeth and suggested that Isl1 plays a role in patterning of dentition as an activator of Bmp4 expression in incisor (distal) areas of the stomatodeal epithelium.
Bu et al. (2009) identified a diverse set of human fetal ISL1-positive cardiovascular progenitors that give rise to the cardiomyocyte, smooth muscle, and endothelial cell lineages. Using 2 independent transgenic and gene targeting approaches in human embryonic stem cell lines, they showed that purified ISL1-positive primordial progenitors are capable of self-renewal and expansion before differentiation into the 3 major cell types in the heart.
Peng et al. (2013) identified a population of multipotent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2 (147870), Gli1 (165220), and Isl1. Peng et al. (2013) showed that CPPs arise from cardiac progenitors before lung development. Lineage tracing and clonal analysis demonstrates that CPPs generate the mesoderm lineages within the cardiac inflow tract and lung, including cardiomyocytes, pulmonary vascular and airway smooth muscle, proximal vascular endothelium, and pericyte-like cells. CPPs are regulated by hedgehog (SHH; 600725) expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart. Peng et al. (2013) concluded that taken together, their studies identified a novel population of multipotent cardiopulmonary progenitors that coordinates heart and lung codevelopment that is required for adaptation to terrestrial existence.
By genetic linkage analysis, Tanizawa et al. (1994) mapped the ISL1 gene on 5q, 12.8 cM from D5S395 on one side and 11.6 cM from D5S407 on the other side. A diagram presented by Tanizawa et al. (1994) indicated that D5S395 and D5S407 are located in the proximal part of 5q, with D5S395 nearer the centromere. Linkage analyses in 15 nonglucokinase MODY (125850) pedigrees indicated that linkage could be rejected over a distance of 15 cM.
Shimomura et al. (2000) found a nonsense mutation (Q310X) in the ISL1 gene in a Japanese patient with type II diabetes and a strong family history. The mutation led to decreased activity of the islet-1 transcription factor and thus may have been pathogenic. However, as indicated by Fajans et al. (2001), additional genetic and clinical studies were required to determine whether mutations in ISL1 are the cause of another subtype of MODY.
Stolfi et al. (2010) found that heart progenitor cells of the simple chordate Ciona intestinalis generated precursors of the atrial siphon muscles. These precursors expressed Islet and Tbx1 (602054)/Tbx10 (604648), evocative of the splanchnic mesoderm that produces the lower jaw muscles and second heart field of vertebrates. Stolfi et al. (2010) presented evidence identifying the transcription factor Coe (EBF1; 164343) as a critical determinant of atrial siphon muscle fate. They proposed that the last common ancestor of tunicates and vertebrates possessed multipotent cardiopharyngeal muscle precursors, and that their reallocation might have contributed to the emergence of the second heart field.
Cai et al. (2003) observed that mice with a homozygous null mutation in the Isl1 gene exhibited growth retardation at embryonic day 9.5 and died at about day 10.5. The hearts of Isl1-null mice were severely abnormal, appearing misshapen and unlooped. Cai et al. (2003) determined that a progenitor cell population expressing Isl1 gave rise to the right ventricle, a subset of left ventricular cells, and a large number of atrial cells. Cells not expressing Isl1 gave rise to most of the left ventricle as well as atrial cells. The authors concluded that Isl1 expression defines cardiac progenitor cell populations and is required for normal cardiac development and asymmetry.
Bu, L., Jiang, X., Martin-Puig, S., Caron, L., Zhu, S., Shao, Y., Roberts, D. J., Huang, P. L., Domian, I. J., Chien, K. R. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460: 113-117, 2009. [PubMed: 19571884] [Full Text: https://doi.org/10.1038/nature08191]
Cai, C.-L., Liang, X., Shi, Y., Chu, P.-H., Pfaff, S. L., Chen, J., Evans, S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev. Cell 5: 877-889, 2003. [PubMed: 14667410] [Full Text: https://doi.org/10.1016/s1534-5807(03)00363-0]
Fajans, S. S., Bell, G. I., Polonsky, K. S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New Eng. J. Med. 345: 971-980, 2001. [PubMed: 11575290] [Full Text: https://doi.org/10.1056/NEJMra002168]
Laugwitz, K.-L., Moretti, A., Lam, J., Gruber, P., Chen, Y., Woodard, S., Lin, L.-Z., Cai, C.-L., Lu, M. M., Reth, M., Platoshyn, O., Yuan, J. X.-J., Evans, S., Chien, K. R. Postnatal isl1-positive cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433: 647-653, 2005. Note: Erratum: Nature 446: 934 only, 2007. [PubMed: 15703750] [Full Text: https://doi.org/10.1038/nature03215]
Lee, S.-K., Pfaff, S. L. Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors. Neuron 38: 731-745, 2003. [PubMed: 12797958] [Full Text: https://doi.org/10.1016/s0896-6273(03)00296-4]
Mitsiadis, T. A., Angeli, I., James, C., Lendahl, U., Sharpe, P. T. Role of islet1 in the patterning of murine dentition. Development 130: 4451-4460, 2003. [PubMed: 12900460] [Full Text: https://doi.org/10.1242/dev.00631]
Peng, T., Tian, Y., Boogerd, C. J., Lu, M. M., Kadzik, R. S., Stewart, K. M., Evans, S. M., Morrisey, E. E. Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500: 589-592, 2013. [PubMed: 23873040] [Full Text: https://doi.org/10.1038/nature12358]
Shimomura, H., Sanke, T., Hanabusa, T., Tsunoda, K., Furuta, H., Nanjo, K. Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49: 1597-1600, 2000. [PubMed: 10969846] [Full Text: https://doi.org/10.2337/diabetes.49.9.1597]
Stolfi, A., Gainous, T. B., Young, J. J., Mori, A., Levine, M., Christiaen, L. Early chordate origins of the vertebrate second heart field. Science 329: 565-568, 2010. [PubMed: 20671188] [Full Text: https://doi.org/10.1126/science.1190181]
Tanizawa, Y., Riggs, A. C., Dagogo-Jack, S., Vaxillaire, M., Froguel, P., Liu, L., Donis-Keller, H., Permutt, M. A. Isolation of the human LIM/homeodomain gene islet-1 and identification of a simple sequence repeat polymorphism. Diabetes 43: 935-941, 1994. Note: Erratum: Diabetes 43: 1171 only, 1994. [PubMed: 7912209] [Full Text: https://doi.org/10.2337/diab.43.7.935]
Tsuchida, T., Ensini, M., Morton, S. B., Baldassare, M., Edlund, T., Jessell, T. M., Pfaff, S. L. Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79: 957-970, 1994. [PubMed: 7528105] [Full Text: https://doi.org/10.1016/0092-8674(94)90027-2]