Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration

Facchinello, Nicola; Tarifeño-Saldivia, Estefanía; Schiavone, Marco; Peron, Margherita; Mongera, Alessandro; Ek, Olivier; Schmitner, Nicole; Meyer, Dirk; Peers, Bernard; Tiso, Natascia; Argenton, Francesco

doi:10.1038/s41598-017-09867-x

Cited by 18 publications

(16 citation statements)

References 76 publications

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“…As a signalling pathway highly conserved throughout evolution, the Wnt signalling pathway plays a key role in pancreatic development in mice, rats, and humans [31][32][33][34][35]. Studies have shown that the Wnt signalling pathway International Journal of Endocrinology regulates the proliferation of islet β-cells and that Wnt3a stimulates insulin secretion in cocultured β-cell lines by upregulating the Pitx2 transcription factors [36].…”

Section: Discussionmentioning

confidence: 99%

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

Jones

Geng

et al. 2020

International Journal of Endocrinology

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Background. Type 2 diabetes mellitus is a serious public health problem worldwide. Accumulating evidence has shown that β-cell dysfunction is an important mechanism underlying diabetes mellitus. e changes in the physiological state of islet stellate cells (ISCs) and the effects of these cells on β cell function play an important role in the development of diabetes. is study aimed at elucidating the mechanism by which ISCs regulate insulin secretion from Min6 cells via the Wnt5a protein. Methods. Glucosestimulated insulin secretion (GSIS) from Min6 cells was examined by estimating the insulin levels in response to high glucose challenge after culture with ISC supernatant or exogenous Wnt5a. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to observe changes in the β-catenin, receptor tyrosine kinase-like orphan receptor 2 (Ror2), Ca (2+)/calmodulin (CaM)-dependent protein kinase II (CamKII), forkhead box O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX1), glucose transporter 2 (Glut2), insulin, and Cask mRNA and protein levels in the Wnt and insulin secretory pathways. Flow cytometry was used to confirm the intracellular Ca 2+ concentration in Min6 cells. Results. We observed a significant increase in insulin secretion from Min6 cells cocultured in vitro with supernatant from db/m mouse ISCs compared to that from Min6 cells cocultured with supernatant from db/db mouse ISCs; e intracellular Ca 2+ concentration in Min6 cells increased in cultured in vitro with supernatant from db/m mouse ISCs and exogenous Wnt5a compared to that from control Min6 cells. Culture of Min6 cells with exogenous Wnt5a caused a significant increase in pCamKII, pFoxO1, PDX-1, and Glut2 levels compared to those in Min6 cells cultured alone; this treatment further decreased Ror2 and Cask expression but did not affect β-catenin expression. Conclusion. ISCs regulate insulin secretion from Min6 cells through the Wnt5a protein-induced Wntcalcium and FoxO1-PDX1-GLUT2-insulin signalling cascades.

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Section: Discussionmentioning

confidence: 99%

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

Jones

Geng

et al. 2020

International Journal of Endocrinology

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“…Moreover, TCF7L2 connected mitochondrial biogenesis and metabolic shift with stem cell commitment to hepatic differentiation. However, its impact on cancer cell glycolysis is a phenomenon that has seldom been discussed 20 , 21 . Thus, it piqued our interest to explore whether TCF7L2 was related to, and regulated expression of, glycolytic genes to affect clinical prognoses in patients with PDAC.…”

Section: Discussionmentioning

confidence: 99%

TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer

Xiang

Qin

et al. 2018

Cell Death Dis

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Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/β-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a β-catenin transcriptional partner, plays a vital role in the Wnt/β-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF-1α). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing 18FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer.

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“…Specifically, we found that miR-7 over-expression in human neural progenitor cells down-regulated bHLH genes TCF4 and TCF12, both involved in neural development, as well as TCF7L2, encoding a Wnt/β-catenin pathway TCF/LEF effector [37,38]. The top hits TCF4 and TCF12 belong to the bHLH group of transcription factors, with TCF4 playing a role in the pontine nucleus development [39], and TCF12 involved in mDA specification [4] and neural stem cell proliferation [40].…”

Section: Identification and Validation Of Mir-7a Target Genes Includimentioning

confidence: 97%

miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

Adusumilli

Facchinello

Teh

et al. 2020

Cells

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During the development of the central nervous system, the proliferation of neural progenitors and differentiation of neurons and glia are tightly regulated by different transcription factors and signaling cascades, such as the Wnt and Shh pathways. This process takes place in cooperation with several microRNAs, some of which evolutionarily conserved in vertebrates, from teleosts to mammals. We focused our attention on miR-7, as its role in the regulation of cell signaling during neural development is still unclear. Specifically, we used human stem cell cultures and whole zebrafish embryos to study, in vitro and in vivo, the role of miR-7 in the development of dopaminergic (DA) neurons, a cell type primarily affected in Parkinson's disease. We demonstrated that the zebrafish homologue of miR-7 (miR-7a) is expressed in the forebrain during the development of DA neurons. Moreover, we identified 143 target genes downregulated by miR-7, including the neural fate markers TCF4 and TCF12, as well as the Wnt pathway effector TCF7L2. We then demonstrated that miR-7 negatively regulates the proliferation of DA-progenitors by inhibiting Wnt/β-catenin signaling in zebrafish embryos. In parallel, miR-7 positively regulates Shh signaling, thus controlling the balance between oligodendroglial and DA neuronal cell fates. In summary, this study identifies a new molecular cross-talk between Wnt and Shh signaling pathways during the development of DA-neurons. Being mediated by a microRNA, this mechanism represents a promising target in cell differentiation therapies for Parkinson's disease.

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Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration

Cited by 18 publications

References 76 publications

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer

miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

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