A Foxo/Notch pathway controls myogenic differentiation and fiber type specification

Kitamura, Tadahiro; Kitamura, Yoichi; Funahashi, Yasuhiro; Shawber, Carrie J.; Castrillón, Diego H.; Kollipara, Ramya; DePinho, Ronald A.; Kitajewski, Jan; Accili, Domenico

doi:10.1172/jci32054

Cited by 253 publications

(282 citation statements)

References 56 publications

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“…Following FOXO1 silencing, a significant decrease in HES1 gene expression and protein abundance was observed in the human fetal islets. These findings are in accord with a recently proposed mechanism describing a functional interaction between FOXO1 and Notch that is required for the regulation of myoblast maintenance and differentiation Data are means ± SEM (n=6 experiments per treatment group for the qRT-PCR assays, n=4 experiments per treatment group for the western blots; *p<0.05 vs control siRNA group) [15]: this model suggests that murine FOXO1 binds to the CSL element within the Hes1 promoter, stabilising the Notch/CSL complex, and thereby enhancing Hes1 transcription [15]. Thus, our present study suggests a second possible mechanism by which FOXO1 may regulate NGN3 levels during human pancreatic development.…”

Section: Discussionsupporting

confidence: 89%

“…More recently, FOXO1 has been reported in murine myoblasts to interact with Notch signalling to regulate hairy and enhancer of split 1 (Hes1) gene expression; HES1 is a well-known repressor of neurogenin 3 (Ngn3 [also known as Neurog3]) [15,16]. These findings suggest that FOXO1 may be involved at multiple steps of murine pancreatic organogenesis [12].…”

Section: Introductionmentioning

confidence: 99%

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Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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Aims/hypothesis Recent studies have demonstrated that in adult murine beta cells the forkhead box O1 (FOXO1) transcription factor regulates proliferation and stress resistance. However, the role of FOXO1 during pancreatic development remains largely unknown. The present study aimed to characterise the expression of the FOXO1 transcription factor in the early to mid-gestation human fetal pancreas and to understand its role in islet cell development. Methods Human (8-21 week fetal age) pancreases were examined using immunohistological, quantitative RT-PCR and western blotting. Isolated human (18-21 week) fetal islet epithelial cell clusters were treated with insulin or glucose, or transfected with FOXO1 small interfering RNA (siRNA). Results Nuclear and cytoplasmic FOXO1 were widely produced during human fetal endocrine pancreatic development, co-localising in cells with the transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (NGN3) as well as cytokeratin 19 (CK19), insulin and glucagon. Treatment with exogenous insulin (50 nmol/l) induced the nuclear exclusion of FOXO1 in both cytokeratin 19 (CK19) + (p<0.01) and insulin + cells (p<0.05) in parallel with increased phospho-Akt (p<0.05) production. siRNA knockdown of FOXO1 significantly increased the number of NGN3 + (p<0.01) and NK6 homeobox 1 (NKX6-1) + (p<0.05) cells in parallel with increases in insulin gene expression (p<0.03) and C-peptide + cells (p<0.05) and reduced levels of hairy and enhancer of split 1 (HES1) (p<0.01). Conclusions/interpretation Our results indicate that FOXO1 may negatively regulate beta cell differentiation in the human fetal pancreas by controlling critical transcription factors, including NGN3 and NKX6-1. These data suggest that the manipulation of FOXO1 levels may be a useful tool for improving cell-based strategies for the treatment of diabetes.Keywords Human fetal pancreas . Human islet epithelial cell clusters . Islet transcription factors . Nuclear FOXO1 . FOXO1 siRNA Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

et al. 2009

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“…It is not only in SMCs where FOXO transcription play a role in regulating myogenesis, it has recently been demonstrated that Foxo1 can also regulate myogenic differentiation in skeletal muscle (Kitamura et al, 2007). The Notch pathway plays a critical role in muscle differentiation during embryogenesis (Luo et al, 2005).…”

Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

“…Accili and coworkers made the connection that Foxo gain-offunction has similar effects on myoblast differentiation as Notch1 activation, while Foxo1 ablation in mice has a similar phenotype to Notch1 (À/À) animals (Krebs et al, 2000;Hosaka et al, 2004). In C2C12 cells, growth factor withdrawal results in myogenic conversion and ectopic expression of a constitutively active Foxo1 mutant, blocked this effect in a DNA-binding independent manner (Kitamura et al, 2007). Constitutively active Notch1 had identical effects in blocking myoblast differentiation, and Foxo siRNA rescued the inhibition.…”

Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

FOXO-binding partners: it takes two to tango

van der Vos,

Coffer

2008

Oncogene

187

161

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Modulation FOXO transcription factor activities can lead to a variety of cellular outputs resulting in changes in proliferation, apoptosis, differentiation and metabolic responses. Although FOXO proteins all contain an identical DNA-binding domain their cellular functions appear to be distinct, as exemplified by differences in the phenotype of Foxo1, Foxo3 and Foxo4 null mutant mice. While some of these differences may be attributable to the differential expression patterns of these transcription factors, many cells and tissues express several FOXO isoforms. Recently it has become clear that FOXO proteins can regulate transcriptional responses independently of direct DNA-binding. It has been demonstrated that FOXOs can associate with a variety of unrelated transcription factors, regulating activation or repression of diverse target genes. The complement of transcription factors expressed in a particular cell type is thus critical in determining the functional end point of FOXO activity. These interactions greatly expand the possibilities for FOXO-mediated regulation of transcriptional programmes. This review details currently described FOXO-binding partners and examines the role of these interactions in regulating cell fate decisions.

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“…Although muscle function was not investigated, with such levels of chimerism, one would expect improvement in muscle function following the transplantation of these cells. The mechanism by which activated Notch acts in this study is unclear since this gene is well recognized for its repressive effect on myogenic determination [49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery

Gang

Darabi

Bosnakovski

et al. 2009

Experimental Cell Research

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Mesenchymal stem cell preparations have been proposed for muscle regeneration in musculoskeletal disorders. Although MSCs have great in vitro expansion potential and possess the ability to differentiate into several mesenchymal lineages, myogenesis has proven to be much more difficult to induce. We have recently demonstrated that Pax3, the master regulator of the embryonic myogenic program, enables the in vitro differentiation of a murine mesenchymal stem cell line (MSCB9-Pax3) into myogenic progenitors. Here we show that injection of these cells into cardiotoxin-injured muscles of immunodeficient mice leads to the development of muscle tumors, resembling rhabdomyosarcomas. We then extended these studies to primary human mesenchymal stem cells (hMSCs) isolated from bone marrow. Upon genetic modification with a lentiviral vector encoding PAX3, hMSCs activated the myogenic program as demonstrated by expression of myogenic regulatory factors. Upon transplantation, the PAX3-modified MSCs did not generate rhabdomyosarcomas but rather, resulted in donor-derived myofibers. These were found at higher frequency in PAX3-transduced hMSCs than in mock-transduced MSCs. Nonetheless, neither engraftment of PAX3-modified or unmodified MSCs resulted in improved contractility.Thus these findings suggest that limitations remain to be overcome before MSC preparations result in effective treatment for muscular dystrophies.

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A Foxo/Notch pathway controls myogenic differentiation and fiber type specification

Cited by 253 publications

References 56 publications

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

FOXO-binding partners: it takes two to tango

Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery

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