RGD Reference Report - The LIM homeodomain protein ISL1 mediates the function of TCF7L2 in pancreatic beta cells. - Rat Genome Database

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The LIM homeodomain protein ISL1 mediates the function of TCF7L2 in pancreatic beta cells.

Authors: Shao, Weijuan  Szeto, Vivian  Song, Zhuolun  Tian, Lili  Feng, Zhong-Ping  Nostro, M Cristina  Jin, Tianru 
Citation: Shao W, etal., J Mol Endocrinol. 2018 Jul;61(1):1-12. doi: 10.1530/JME-17-0181. Epub 2018 Apr 20.
RGD ID: 243065231
Pubmed: PMID:29678908   (View Abstract at PubMed)
DOI: DOI:10.1530/JME-17-0181   (Journal Full-text)

Pancreatic β-cell Tcf7l2 deletion or its functional knockdown suggested the essential role of this Wnt pathway effector in controlling insulin secretion, glucose homeostasis and β-cell gene expression. As the LIM homeodomain protein ISL1 is a suggested Wnt pathway downstream target, we hypothesize that it mediates metabolic functions of TCF7L2. We aimed to determine the role of ISL1 in mediating the function of TCF7L2 and the incretin hormone GLP-1 in pancreatic β-cells. The effect of dominant negative TCF7L2 (TCF7L2DN) mediated Wnt pathway functional knockdown on Isl1 expression was determined in βTCFDN mouse islets and in the rat insulinoma cell line INS-1 832/13. Luciferase reporter assay and chromatin immunoprecipitation were utilized to determine whether Isl1 is a direct downstream target of Tcf7l2 TCF7L2DN adenovirus infection and siRNA-mediated Isl1 knockdown on β-cell gene expression were compared. Furthermore, Isl1 knockdown on GLP-1 stimulated β-catenin S675 phosphorylation and insulin secretion was determined. We found that TCF7L2DN repressed ISL1 levels in βTCFDN islets and the INS-1 832/13 cell line. Wnt stimulators enhanced Isl1 promoter activity and binding of TCF7L2 on Isl1 promoter. TCF7L2DN adenovirus infection and Isl1 knockdown generated similar repression on expression of β-cell genes, including the ones that encode GLUT2 and GLP-1 receptor. Either TCF7L2DN adenovirus infection or Isl1 knockdown attenuated GLP-1-stimulated β-catenin S675 phosphorylation in INS-1 832/13 cells or mouse islets and GLP-1 stimulated insulin secretion in INS-1 832/13 or MIN6 cells. Our observations support the existence of TCF7L2-ISL1 transcriptional network, and we suggest that this network also mediates β-cell function of GLP-1.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Isl1Ratpositive regulation of calcium ion import  IMP  RGD 
Isl1Ratpositive regulation of insulin secretion  IMP  RGD 
Isl1Ratpositive regulation of peptidyl-serine phosphorylation  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Isl1  (ISL LIM homeobox 1)

Additional Information