2005 Fiscal Year Final Research Report Summary
Molecular mechanism for regulation of glucose metabolism by Otx3
| Project/Area Number |
15590929
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Metabolomics
|
|---|
| Research Institution | Kobe University (2004-2005)
Chiba University (2003) |
|---|
Principal Investigator |
MIKI Takashi Kobe University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助教授 (50302568)
|
|---|
| Project Period (FY) |
2003 – 2005
|
| Keywords | Otx3 / transcription factor / energy metabolism / homeodomain |
|---|
| Research Abstract |
The Otx family of transcriptional repressors plays a critical role in the development of brain. We previously identified a novel member of the Otx family Otx3,which is expressed in developing brain and adult pancreatic ss-cells. In this project, we aimed at clarifying the function of Otx3 by elucidating biochemical properties of Otx3 and by analyzing Otx3 knockout mice.
Biochemical experiments revealed that Otx3 formed heterodimer with Otx2 on P3C (TAATCCGATTA) sequence and repressed the Otx2-mediated transactivation. The 156 amino acid region (residue 1-156) of Otx3 is required for its repressor activity and was shown to interact directly with Otx2. Co-localization of Otx3 and Otx2 in the brain section was confirmed by in situ hybridization. We have also identified the consensus binding sequence [TAATCCGATTA and TAATCC(N2-4)TAATCC] of Otx3 using the random oligonucleotide selection method.
To clarify the physiological roles of Otx3,Otx3 knockout (KO) mice were generated. KO mice are viable and lack gross abnormality in the morphology of brain including the expression patterns of molecular markers of anterior/posterior axis of the brain. Interestingly, KO mice exhibited marked hypoglycemia after food deprivation and decreased insulin secretion in response to oral glucose load, suggesting that KO mice are defective in the regulation of glucose metabolism. Although Otx3 is expressed in adult pancreatic islets and a pancreatic ss-cell line MIN6, insulin secretory response to glucose was not affected in the perfusion experiments of KO pancreata, suggesting that the insulin-secretory function of KO ss-cells remains normal. By contrast, KO mice are shown to be hypersensitive to exogenous insulin. Considering that Otx3 is expressed almost exclusively in brain except for pancreatic ss-cells, dysfunction of Otx3 in brain is suggested to cause the abnormal regulation of glucose homeostasis.
|
