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 SOX9
Homo sapiens
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Homo sapiens
 Pax6
Mus musculus
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Homo sapiens
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Mus musculus
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Mus musculus
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Mus musculus
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Mus musculus
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Overview

Islet-1 (Isl1) is a LIM-Homeodomain transcription factor, initially identified as an insulin gene enhancer binding protein [1]. Isl1 exhibits a distinct expression pattern during development in multiple cell types, including neurons of forebrain [2], spinal motor neurons [3-5], neural retina, neurons in the peripheral nervous system, pancreatic islet cells and dorsal pancreatic mesenchymal cells [1, 6-8], pharyngeal/ foregut endoderm and lateral plate splanchnic mesoderm [9-12]. Recent genetic studies have revealed essential roles of Isl1 in cell specification, differentiation and survival. Isl1 is required for development of subset of forebrain cholinergic neurons, and retinal ganglion cells, and retinal Bipolar and cholinergic amacrine cells [13-15]. Isl1 is also required for the pancreatic development [6]. In spinal motor neuron, combinatory expression of LIM domain transcription factors, including Isl1, Lim3, Lmo4 and NLI/Ldb1, which form highly ordered complexes, referred as to LIM codes, play essential role in specification of motor neuron versus V2 interneuron [5, 16-18]. Isl1 is expressed in sensory neurons of the DRG and trigeminal ganglia and plays essential roles in coordination of sensory neuron gene program that ensure neuronal survival and differentiation [19]. Isl1 marks the cardiogenetic progenitors of the second heart field and is required for proliferation, differentiation, migration and survival of these progenitors [9, 20]. Heat formation is under tight control of multiple signaling pathways and complex transcriptional network, Isl1 appears to play a central role in these cardiac genetic programs. Isl1 is downstream of Wnt/-catenin and FGF8 signaling but upstream of BMP4, BMP7, FGF10 and Shh [21-25]. Isl1 is a direct downstream target of Forkhead transcription factors [26]. Mef2c has been identified as a direct downstream target of Isl1. Binding of Isl1 as well as GATA4 to their respective binding site in Mef2c cardiac enhancer is required for cardiac expression of this enhancer [27]. A GATA4 and Isl1 binding sites have been found in a cardiac enhancer upstream of Nkx2.5 gene and expression of this enhance in cardiac region is dependent on GATA4 and Isl1 [28, 29]. In addition, Isl1 is known to bind and regulate the promoters of the insulin, glucagon and somatostatin genes [1, 30-32]. Isl1 gene has 6 exons and is located in chromosome 13 in mouse and chromosome 5 in human. One alternatively spliced variant of Isl1 has been identified from mouse beta-cell, but functional consequence of this alternative splicing is not clear [33]. In addition, a heterozygous nonsense mutation in isl1 gene that leads to a C-terminal truncation of Isl1 protein, was found in one patient with type 2 diabetes [34].

References

1. Karlsson, O., et al., 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. Nature, 1990. 344(6269): p. 879-82. 2. Wang, H.F. and F.C. Liu, Developmental restriction of the LIM homeodomain transcription factor Islet-1 expression to cholinergic neurons in the rat striatum. Neuroscience, 2001. 103(4): p. 999-1016. 3. Ericson, J., et al., Early stages of motor neuron differentiation revealed by expression of homeobox gene Islet-1. Science, 1992. 256(5063): p. 1555-60. 4. Tsuchida, T., et al., Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell, 1994. 79(6): p. 957-70. 5. Thaler, J.P., et al., A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron, 2004. 41(3): p. 337-50. 6. Ahlgren, U., et al., Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature, 1997. 385(6613): p. 257-60. 7.Dong, J., S.L. Asa, and D.J. Drucker, Islet cell and extrapancreatic expression of the LIM domain homeobox gene isl-1. Mol Endocrinol, 1991. 5(11): p. 1633-41. 8. Thor, S., et al., The homeodomain LIM protein Isl-1 is expressed in subsets of neurons and endocrine cells in the adult rat. Neuron, 1991. 7(6): p. 881-9. 9.Cai, C.L., et al., Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell, 2003. 5(6): p. 877-89. 10. Park, E.J., et al., An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart. Development, 2008. 135(21): p. 3599-610. 11. Sun, Y., et al., Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev Biol, 2007. 304(1): p. 286-96. 12. Yuan, S. and G.C. Schoenwolf, Islet-1 marks the early heart rudiments and is asymmetrically expressed during early rotation of the foregut in the chick embryo. Anat Rec, 2000. 260(2): p. 204-7. 13. Elshatory, Y., et al., Islet-1 controls the differentiation of retinal bipolar and cholinergic amacrine cells. J Neurosci, 2007. 27(46): p. 12707-20. 14. Elshatory, Y. and L. Gan, The LIM-homeobox gene Islet-1 is required for the development of restricted forebrain cholinergic neurons. J Neurosci, 2008. 28(13): p. 3291-7. 15. Pan, L., et al., ISL1 and BRN3B co-regulate the differentiation of murine retinal ganglion cells. Development, 2008. 135(11): p. 1981-90. 16. Pfaff, S.L., et al., Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell, 1996. 84(2): p. 309-20. 17. Song, M.R., et al., Islet-to-LMO stoichiometries control the function of transcription complexes that specify motor neuron and V2a interneuron identity. Development, 2009. 136(17): p. 2923-32. 18. Thaler, J.P., et al., LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell, 2002. 110(2): p. 237-49. 19. Sun, Y., et al., A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs. Nat Neurosci, 2008. 11(11): p. 1283-93. 20. Kwon, C., et al., A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol, 2009. 11(8): p. 951-7. 21. Black, B.L., Transcriptional pathways in second heart field development. Semin Cell Dev Biol, 2007. 18(1): p. 67-76. 22. Ai, D., et al., Canonical Wnt signaling functions in second heart field to promote right ventricular growth. Proc Natl Acad Sci U S A, 2007. 104(22): p. 9319-24. 23. Cohen, E.D., et al., Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling. J Clin Invest, 2007. 117(7): p. 1794-804. 24. Lin, L., et al., Beta-catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis. Proc Natl Acad Sci U S A, 2007. 104(22): p. 9313-8. 25. Park, E.J., et al., Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling. Development, 2006. 133(12): p. 2419-33. 26. Kang, J., et al., Isl1 is a direct transcriptional target of Forkhead transcription factors in second heart field-derived mesoderm. Dev Biol, 2009. 27. Dodou, E., et al., Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development, 2004. 131(16): p. 3931-42. 28. Lien, C.L., et al., Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. Development, 1999. 126(1): p. 75-84. 29. Takeuchi, J.K., et al., Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development. Development, 2005. 132(10): p. 2463-74. 30. Leonard, J., et al., The LIM family transcription factor Isl-1 requires cAMP response element binding protein to promote somatostatin expression in pancreatic islet cells. Proc Natl Acad Sci U S A, 1992. 89(14): p. 6247-51. 31. Wang, M. and D.J. Drucker, The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription. J Biol Chem, 1995. 270(21): p. 12646-52. 32. Zhang, H., et al., The LIM-Homeodomain Protein ISL1 Activates Insulin Gene Promoter Directly through Synergy with BETA2. J Mol Biol, 2009. 33. Ando, K., et al., Isolation and characterization of an alternatively spliced variant of transcription factor Islet-1. J Mol Endocrinol, 2003. 31(3): p. 419-25. 34. Shimomura, H., et al., Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes, 2000. 49(9): p. 1597-600.

Figures
No annotation is available in this section for this article. The content below is taken from a related TF, Isl1 (Mus musculus).
FIGURE 1 Expression of Isl1 in Mouse Embryo and Role of Isl1 in Cardiac Genetic Networks
A. Isl1 exhibits a distinct expression pattern during development in multiple cell types, including neurons in the central and peripheral nervous systems and cardiogenic region. B. Isl1 play an central role in genetic networks that regulate cardiac development and function.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.