Hong Fu

..By sorting and analyzing proliferating hepatocytes, they provide evidence for their transient dedifferentiation...

..The DNA damage response is a barrier to efficient β-cell proliferation in vitro, and we suggest its evaluation in all attempts to stimulate β-cell replication as an approach to diabetes treatment...

..Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype...

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..2 during the major wave of endocrine and exocrine cell differentiation, we assessed gene expression changes that occur in the absence of Nkx2.2 at the onset of the secondary transition in the developing pancreas...

..Generation of new prediction methods that are based on protein binding data, but do not rely on these models may improve prediction sensitivity and specificity...

..Their new mouse model should aid in the development of improved immunoregulatory strategies and in the elucidation of the molecular pathways that govern beta cell regeneration...

..We show that this PancChip is highly enriched for genes expressed in the endocrine pancreas. The mouse and human clone sets and corresponding arrays will be important resources for diabetes research...

..The Foxa1/Foxa2 model is the first of a completely "liver-less mouse" and provides strong evidence for the competence model of hepatic induction...

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..HNF3 alpha is required for the full activation of glucagon in the pancreas, whereas HNF3 gamma induces the activation of gluconeogenic enzymes to prevent hypoglycemia during fasting...

..pros activity, hence, provides a critical regulatory link between neuronal lineage development and transcriptional regulation of cell cycle regulatory genes...

..We also showed that HNF3alpha could bind to and transactivate the proglucagon gene promoter. These observations invoke a central role for HNF3alpha in the regulatory control of islet genes essential for glucose homeostasis in vivo...

..A recent letter to Nature suggests that a switch from early gluconeogenic gene activation via CRTC2 (also known as TORC2) to late action of FOXO1 is critical to this process...

..Thus, we have established Foxa2 as an essential activator of genes that function in multiple pathways governing insulin secretion...

..In addition, ngn3(-/-) mice display intestinal metaplasia of the gastric epithelium. Thus, ngn3 is required for the differentiation of enteroendocrine cells in the stomach and the maintenance of gastric epithelial cell identity...

..Overall, our studies demonstrate that HNF6 binds to and regulates its target promoters in vivo in the presence and absence of Foxa2...

..Alteration in the composition of the gastric epithelium may play a role in influencing the microenvironment to engender susceptibility to carcinogens...

..These data represent the first in vivo demonstration that Foxa2 acts upstream of Pdx1 in the differentiated beta-cell...

..Our data provide genetic evidence that HNF-4alpha is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel...

..By marker gene analysis, we show that the expression of the alpha-cell transcription factors Arx, Pax6, and Brn4 does not require Foxa2 in the transcriptional hierarchy governing alpha-cell differentiation...

..Collectively, these results provide genetic evidence supporting a role for CRTC2 in the transcriptional response to fasting, but indicate only a limited contribution of this cofactor to the maintenance of glucose homeostasis...

..An additional winged-helix protein, Foxo1, contributes to pancreatic beta-cell function by regulating the Pdx1 gene, which is required for pancreatic development in cooperation with Foxa2...

..Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight...

..We conclude that Cdx2 controls important aspects of intestinal identity and development, and that this function is largely independent of the enteric Hox code...

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..The finding of separate pathways for endoderm tissue specification and growth provides insights for guiding cellular regeneration and stem cell differentiation...

..Furthermore, expression of both Foxf1 and Foxl1 is reduced in the Gli2/Gli3 mutant gut. These results provide compelling evidence that Foxf1 and Foxl1 are mediators of the Hh (endoderm) to mesoderm signaling pathway...

..The epithelial zinc-finger transcription factor Klf4 (formerly GKLF) regulates cellular proliferation and differentiation in vitro. Klf4 null mice die by postnatal day 1 and show changes in epithelial differentiation of skin and colon...

..EPConDB provides database queries and tools to examine the relationship between a gene, its transcriptional regulation, protein function and expression in pancreatic tissues...

..All other epithelial cell types are present in the colon of Klf4(-/-) mice. In summary, Klf4 plays a crucial role in colonic epithelial cell differentiation in vivo...

..Our data suggest molecular pathways that may regulate pancreatic growth and offer a unique set of candidate genes to target in the development of therapies aimed at improving pancreatic growth and function...

..Thus, the regulation of Pdx1 expression by Foxa1 and Foxa2 is a key early event controlling the expansion and differentiation of the pancreatic primordia...

..5 through adulthood in mice. The clone set and corresponding array are useful resources for diabetes research...

..We conclude that Foxa2 is required for execution of the hepatic gluconeogenic program by integrating the transcriptional response of the hepatocyte to hormonal stimulation...

..Thus we identified, for the first time, a link between a mesenchymal factor, Foxl1, and the regulation of a specific epithelial transport process...

..These findings are helping to guide our decisions on what labeling method to use for subsequent studies, based on the purpose of a specific study and its limitations in terms of available material...

..We summarize the salient features of the evolution of the Fox gene family and highlight the diverse contribution of various Fox subfamilies to developmental processes, from organogenesis to speech acquisition...

..Our data suggest that Foxa1/2 function as terminators of bile duct expansion in the adult liver through inhibition of IL-6 expression...

..Together, these results indicate that HNF-4alpha is essential for the physiological expansion of adult beta-cell mass in response to increased metabolic demand...

..CONCLUSION: We propose that Foxl1 is a bona fide marker of the facultative progenitor cell in the mouse liver...

..CONCLUSION: Beta-catenin regulates multiple, critical events during the process of hepatic morphogenesis, including hepatoblast maturation, expansion, and survival, making it indispensable to survival...

..Thus, Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis...

..We suggest a unique biological role for CTF18 in mammalian germ cell development based on its mammalian germline expression, high degree of evolutionary conservation, and role in DNA replication and chromosomal stability in yeast...

..This allowed us to identify a large cluster of genes controlling mitotic spindle assembly and checkpoint control at the 40-h time point as regulated at the mRNA level in vivo...

..Cdx2 induces differentiation of intestinal epithelial cells in vitro; therefore, we sought to establish whether a causal relationship exists between Cdx2 activation and intestinal metaplasia...

..These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of beta-cell-specific secretory and metabolic pathways...

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..Chromatin immunoprecipitation assays indicate that UCP2 is a direct transcriptional target of Foxa1 in vivo. Thus, we have identified a novel function for Foxa1 in the regulation of oxidative phosphorylation in pancreatic beta-cells...

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..Interestingly, when we investigated the novel transcripts for their overlap with noncoding microRNAs, we found that 1 of the novel transcripts overlapped a known microRNA gene...

..These findings suggest that Klf4 might play an important role in testicular differentiation in mammals...

..Conclusion: These results indicate that Notch signaling in the liver is sensitive to Jag1 gene dosage and suggest a role for the Notch pathway in postnatal growth and morphogenesis of bile ducts...

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..We aimed to quantify the complete miRNA expression profile of the mammalian intestinal mucosa and to determine the contribution of miRNAs to intestinal homeostasis using genetic means...

..Expression of the Notch modifier Manic Fringe (Mfng) is limited to endocrine precursors, providing a possible explanation for the inhibition of Notch signaling by Jag1 during mid-gestation embryonic pancreas development...

..Efforts to differentiate insulin-producing beta-cells from progenitor or stem cells require knowledge of the transcriptional programs that regulate the development of the endocrine pancreas...

..Together, our results further our understanding of the GR and its targets, and provide the basis for more targeted glucocorticoid therapies...

..Our results suggest a molecular explanation for the hyperinsulinemia hypoglycemic seen in patients with SCHAD deficiency...

..This notion is supported by recent genetic studies linking HNF-4alpha to the much more common late-onset type 2 diabetes...

..In summary, we have identified Foxa3 as a transcriptional regulator with a dominant phenotype in germ cell maintenance and suggest FOXA3 as a potential candidate gene for subfertility in man...

..PANDER-induced downregulation of CDKN1A expression coupled with induced CASP3-activation may serve a central role in islet cell death and offers further insight into the mechanisms of cytokine-induced beta-cell apoptosis...

..This is accentuated during diet-induced obesity, when Igfbp5-deficient mice have increased adiposity compared with wild-type mice on the same diet. These studies reveal a novel role for Igfbp5 in the control of growth and metabolism...

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..These findings suggest Foxa1/a2 as critical factors in the differentiation of gut epithelial cells...

..We show that Foxa2 interacts with different transcription factors to achieve gene expression responses appropriate for each physiologic state...

..We not only provide a better understanding of the mechanisms of Foxa2 regulation but also introduce a novel method for identification of different cis-regulatory modules involving a single factor...

..Up to 40% of Alagille syndrome patients also display exocrine pancreatic insufficiency, the pathobiology of which is unknown. Additionally, no mouse model recapitulating this aspect of the disease has been reported...

..These findings indicate that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology...

..Analysis of factor binding in multiple species may be necessary to distinguish apparent species-unique noise and reveal functionally relevant information...

..It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4alpha might be required for development of the gut...

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..Foxa family members regulate signaling and transcriptional programs required for morphogenesis and cell differentiation during formation of the lung...

..Foxa2 therefore plays an integral role in the formation of axial mesendoderm, which is required to maintain the specification of the forebrain and the anterior definitive endoderm...

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..Foxa2 regulates a complex pulmonary program of epithelial cell maturation required for transition to air breathing at birth...

..These findings demonstrate that Klf4 regulates B cell number and activation-induced B cell proliferation through directly acting on the promoter of cyclin D2...

..We additionally show that many Pdx-1 targets also interact with NeuroD1/BETA2, including the micro-RNA miR-375, a known regulator of insulin secretion...

..Taken together, we have demonstrated that Klf4 plays a critical role in regulating expression of SMC differentiation markers and proliferation of SMCs in vivo in response to vascular injury...

..Further study of the unique targets of cyclin D1 should provide further insight into its prominent role in proliferation, growth and cancer...

..In addition, we show that expression of FOXA2 is markedly decreased in liver samples from individuals with different cholestatic syndromes, suggesting that reduced FOXA2 abundance could exacerbate the injury...

..Collectively, our findings indicate that KLF4 has growth-suppressive properties in B cells but might be redundant with other members of the KLF family in maintaining B cell quiescence...

..FOXA2 is required for alveolarization and regulates airway epithelial cell differentiation in the postnatal lung...

..The altered expression of Hnf4alpha, Hnf6 and Hnf1beta in Hhex conditional null mice suggests that Hhex is an essential component of the genetic networks regulating hepatoblast differentiation and intrahepatic bile duct morphogenesis...

..Together, these results demonstrate that progenitors that have the potential to give rise to insulin-expressing cells can be derived from murine embryonic stem cells...

..Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium...

..In summary, KLF4 plays a significant role for proper and timely Sertoli cell differentiation in pubertal mice...

..These data indicate that the activation of beta-catenin is critical for early postnatal liver growth and development...

..These findings identify Foxa3 as a member of the proglucagon gene G2 element binding-protein family that, unlike Foxa1, is not essential for control of islet or intestinal proglucagon gene expression in vivo...

..Together, these studies will further our understanding of the regulatory circuits that control gastrointestinal proliferation in normal development and carcinogenesis. ..

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..The new resources generated through this project will be made available to the NIDDK-funded biotechnology centers and the diabetes research community at large. ..

..Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of transcriptional regulators, or master genes, in proliferation and performance of beta-cells. ..

..Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of transcriptional regulators, or master genes, in proliferation and performance of beta-cells. ..

..Together, this proposal will further our understanding of GI development and cancer, and allow for the development of novel diagnostic and possibly therapeutic tools in the future. ..

..We will determine the "epigenetic", that is not mutation based, changes in the genome of the diabetic beta-cell that cause it to fail. This work will identify new potential drug targets for the treatment of type 2 diabetes. ..

..Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of transcriptional regulators, or master genes, in proliferation and performance of beta-cells. ..

..The new resources generated through this project will be made available to the NIDDK-funded biotechnology centers and the diabetes research community at large. ..

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..Together, these studies will further our understanding of the regulatory circuits that control gastrointestinal proliferation in normal development and carcinogenesis. ..

..Insights gained about the role of HNF3Beta in Beta-cell function could be incorporated into future therapeutic strategies, including gene therapy. ..

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..Together, this proposal will further our understanding of GI development and cancer, and allow for the development of novel diagnostic and possibly therapeutic tools in the future. ..