The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF

Regad, Tarik; Roth, Martin; Bredenkamp, Nicholas; Illing, Nicola; Papalopulu, Nancy

doi:10.1038/ncb1573

Cited by 92 publications

(109 citation statements)

References 35 publications

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“…60), growth factor signaling through FGFR4 may play an important role in hepatic insulin action. In support of this idea, FGFR4 knock-out mice have impaired glucose tolerance (67), and transgenic expression of FGF19 reverses diabetes in the leptin-deficient ob/ob mouse (68).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we wondered whether the bile acid feedback regulation of hepatic CYP7A1 through intestine-derived FGF15 might also target FoxO1 through PI 3-kinase signaling. In fact, a recent report demonstrated that FGF signaling through PI 3-kinase regulates the related FoxG1 protein in the vertebrate forebrain (60). If the FGF19/15 signaling pathway plays a role in the regulation of CYP7A1 during fasting, then either intestinal FGF15 production or hepatic expression of FGFR4 should be decreased by fasting.…”

Section: Fgf19 Inhibits Expression Of Cyp7a1 and Other Foxo1mentioning

confidence: 99%

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FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7␣ hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.Hepatic cholesterol is converted to bile acids, secreted into the gallbladder, and during a meal is released into the small intestine to enhance digestion and absorption of dietary lipids and fat-soluble vitamins. The majority of the bile acid pool (95%) is recycled back to the liver, whereas the remaining 5% is eliminated through fecal excretion (1, 2). This is an important route for the elimination of excess cholesterol and underscores the importance that bile acids play in regulating mammalian cholesterol metabolism. The initial and rate-controlling step in the classic pathway for cholesterol conversion into bile acids is catalyzed by cholesterol 7␣-hydroxylase (CYP7A1).2 CYP7A1 regulation is primarily transcriptional, and expression of its gene is dynamically regulated by hormones and metabolites (2-6). Importantly, bile acids themselves regulate CYP7A1 gene expression through a multicomponent negative feedback pathway. One of the molecular pathways for bile acid regulation is initiated by the activation of the farnesoid X receptor (FXR) responding directly to bile acid agonists (7). Ligand-activated FXR directly binds to a site in the promoter for the small heterodimer partner (SHP) gene and induces expression of SHP mRNA (8, 9). The translated SHP protein lacks the signature nuclear receptor zinc finger DNA binding domain but uses its conserved dimerization motif to form protein-protein contacts with DNA bound activators, usually other nuclear receptors, to inhibit or interfere with their activation potential (10, 11).The first identified target for SHP repression was the CYP7A1 promoter, and SHP was proposed to interfere with activation by the DNA-bound monomeric liver receptor homologue 1 (LRH-1) nucl...

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Section: Discussionmentioning

confidence: 99%

Section: Fgf19 Inhibits Expression Of Cyp7a1 and Other Foxo1mentioning

confidence: 99%

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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“…S2e). RT-qPCR analyses of the isolated cells showed co-expression of neural marker mRNAs (Sox2 and Nestin) 25,26 with Epo mRNA in NEP cells ( Supplementary Fig. S3a).…”

Section: Articlementioning

confidence: 99%

Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

et al. 2013

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Erythropoietin (Epo) supports both primitive erythropoiesis in the yolk sac and definitive erythropoiesis in the fetal liver and bone marrow. Although definitive erythropoiesis requires kidney-and liver-secreted Epo, it is unclear which cells produce Epo for primitive erythropoiesis. Here we find neural Epo-producing (NEP) cells in mid-gestational stage embryos using mouse lines that express green fluorescent protein (GFP) under the Epo gene regulation. In these mice, GFP is expressed exclusively in a subpopulation of neural and neural crest cells at embryonic day 9.0 when Epo-deficient embryos exhibit abnormalities in primitive erythropoiesis. The GFP-positive NEP cells express Epo mRNA and the ex vivo culture of embryonic day 8.5 neural tubes results in the secretion of Epo, which is able to induce the proliferation and differentiation of yolk sac-derived erythroid cells. These results thus suggest that NEP cells secrete Epo and might support the development of primitive erythropoiesis.

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“…The serine phosphorylation status of FOXG1 in ovarian cancer cells was analysed according to Regad et al (2007). Briefly, ovarian cancer cells were collected in NET lysis buffer (50 mM Tris, pH 7.4, 150 mM NaCl and 5 mM EDTA) with 1% NP40, pH 8.0, 0.1 mM PMSF and 1 mM Complete TM protease inhibitor cocktail (Roche).…”

Section: Subcellular Fractionation and Phosphorylation Studiesmentioning

confidence: 99%

Overexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21WAF1/CIP1 expression in ovarian cancer

Chan

Liu

et al. 2009

Br J Cancer

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BACKGROUND: Loss of growth inhibitory response to transforming growth factor-b (TGF-b) is a common feature of epithelial cancers. Recent studies have reported that genetic lesions and overexpression of oncoproteins in TGF-b/Smads signalling cascade contribute to the TGF-b resistance. Here, we showed that the overexpressed FOXG1 was involved in attenuating the anti-proliferative control of TGF-b/Smads signalling in ovarian cancer. METHODS: FOXG1 and p21 WAF1/CIP1 expressions were evaluated by real-time quantitative reverse-transcription polymerase chain reaction (RT -PCR), western blot and immunohistochemical analyses. The effect of FOXG1 on p21 WAF1/CIP1 transcriptional activity was examined by luciferase reporter assays. Cell lines stably expressing or short hairpin RNA interference-mediated knockdown FOXG1 were established for studying the gain-or-loss functional effects of FOXG1. XTT cell proliferation assay was used to measure cell growth of ovarian cancer cells. RESULTS: Quantitative RT -PCR and western blot analyses showed that FOXG1 was upregulated and inversely associated with the expression levels of p21 WAF1/CIP1 in ovarian cancer. The overexpression of FOXG1 was significantly correlated with high-grade ovarian cancer (P ¼ 0.025). Immunohistochemical analysis on ovarian cancer tissue array was further evidenced that FOXG1 was highly expressed and significantly correlated with high-grade ovarian cancer (P ¼ 0.048). Functionally, enforced expression of FOXG1 selectively blocked the TGF-b-induced p21 WAF1/CIP1 expressions and increased cell proliferation in ovarian cancer cells. Conversely, FOXG1 knockdown resulted in a 20 -26% decrease in cell proliferation together with 16 -33% increase in p21 WAF1/CIP1 expression. Notably, FOXG1 was able to inhibit the p21 WAF1/CIP1 promoter activity in a p53-independent manner by transient reporter assays.

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The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF

Cited by 92 publications

References 35 publications

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

Overexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21WAF1/CIP1 expression in ovarian cancer

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