The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo.

Abstract:

:Pax3 is a key transcription factor implicated in development and human disease. To dissect the role of Pax3 in myogenesis and establish whether it is a repressor or activator, we generated loss- and gain-of-function alleles by targeting an nLacZ reporter and a sequence encoding the oncogenic fusion protein PAX3-FKHR into the Pax3 locus. Rescue of the Pax3 mutant phenotypes by PAX3-FKHR suggests that Pax3 acts as a transcriptional activator during embryogenesis. This is confirmed by a Pax reporter mouse. However, mice expressing PAX3-FKHR display developmental defects, including ectopic delamination and inappropriate migration of muscle precursor cells. These events result from overexpression of c-met, leading to constitutive activation of Met signaling, despite the absence of the ligand SF/HGF. Haploinsufficiency of c-met rescues this phenotype, confirming the direct genetic link with Pax3. The gain-of-function phenotype is also characterized by overactivation of MyoD. The consequences of PAX3-FKHR myogenic activity in the limbs and cervical and thoracic regions point to differential regulation of muscle growth and patterning. This gain-of-function allele provides a new approach to the molecular and cellular analysis of the role of Pax3 and of its target genes in vivo.

journal_name

Genes Dev

journal_title

Genes & development

authors

Relaix F,Polimeni M,Rocancourt D,Ponzetto C,Schäfer BW,Buckingham M

doi

10.1101/gad.281203

subject

Has Abstract

pub_date

2003-12-01 00:00:00

pages

2950-65

issue

23

eissn

0890-9369

issn

1549-5477

pii

17/23/2950

journal_volume

17

pub_type

杂志文章
  • Fragile X-related protein and VIG associate with the RNA interference machinery.

    abstract::RNA interference (RNAi) is a flexible gene silencing mechanism that responds to double-stranded RNA by suppressing homologous genes. Here, we report the characterization of RNAi effector complexes (RISCs) that contain small interfering RNAs and microRNAs (miRNAs). We identify two putative RNA-binding proteins, the Dro...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1025202

    authors: Caudy AA,Myers M,Hannon GJ,Hammond SM

    更新日期:2002-10-01 00:00:00

  • SCAMP4 enhances the senescent cell secretome.

    abstract::The senescence-associated secretory phenotype (SASP) is a major trait of senescent cells, but the molecular regulators of SASP factor secretion are poorly understood. Mass spectrometry analysis revealed that secretory carrier membrane protein 4 (SCAMP4) levels were strikingly elevated on the surface of senescent cells...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.313270.118

    authors: Kim KM,Noh JH,Bodogai M,Martindale JL,Pandey PR,Yang X,Biragyn A,Abdelmohsen K,Gorospe M

    更新日期:2018-07-01 00:00:00

  • Genome-wide chromatin footprinting reveals changes in replication origin architecture induced by pre-RC assembly.

    abstract::Start sites of DNA replication are marked by the origin recognition complex (ORC), which coordinates Mcm2-7 helicase loading to form the prereplicative complex (pre-RC). Although pre-RC assembly is well characterized in vitro, the process is poorly understood within the local chromatin environment surrounding replicat...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.247924.114

    authors: Belsky JA,MacAlpine HK,Lubelsky Y,Hartemink AJ,MacAlpine DM

    更新日期:2015-01-15 00:00:00

  • Seven-up, the Drosophila homolog of the COUP-TF orphan receptors, controls cell proliferation in the insect kidney.

    abstract::Morphogenesis of the insect kidney, the Malpighian tubules, is controlled in Drosophila by a single large cell, the tip cell. It has been postulated that this cell sends out a mitogenic signal that induces the division of neighboring cells. The signal and the molecules that receive it have remained elusive. We show th...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.12.12.1781

    authors: Kerber B,Fellert S,Hoch M

    更新日期:1998-06-15 00:00:00

  • G1 cyclin-dependent kinases are insufficient to reverse dE2F2-mediated repression.

    abstract::Here we show that the cell cycle defects of dE2F1-depleted cells depend on the cooperative effects of dE2F2 and DACAPO (DAP), an inhibitor of Cyclin E/cyclin-dependent kinase 2 (CycE/cdk2). The different properties of cells lacking dE2F1/dE2F2 and dE2F1/DAP lead to the surprising observation that dE2F2-mediated repres...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1031803

    authors: Frolov MV,Stevaux O,Moon NS,Dimova D,Kwon EJ,Morris EJ,Dyson NJ

    更新日期:2003-03-15 00:00:00

  • The Lats2 tumor suppressor augments p53-mediated apoptosis by promoting the nuclear proapoptotic function of ASPP1.

    abstract::Apoptosis is an important mechanism to eliminate potentially tumorigenic cells. The tumor suppressor p53 plays a pivotal role in this process. Many tumors harbor mutant p53, but others evade its tumor-suppressive effects by altering the expression of proteins that regulate the p53 pathway. ASPP1 (apoptosis-stimulating...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1954410

    authors: Aylon Y,Ofir-Rosenfeld Y,Yabuta N,Lapi E,Nojima H,Lu X,Oren M

    更新日期:2010-11-01 00:00:00

  • The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism.

    abstract::Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose depriv...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1985910

    authors: Wellen KE,Lu C,Mancuso A,Lemons JM,Ryczko M,Dennis JW,Rabinowitz JD,Coller HA,Thompson CB

    更新日期:2010-12-15 00:00:00

  • Genetics and biology of pancreatic ductal adenocarcinoma.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biol...

    journal_title:Genes & development

    pub_type: 杂志文章,评审

    doi:10.1101/gad.1415606

    authors: Hezel AF,Kimmelman AC,Stanger BZ,Bardeesy N,Depinho RA

    更新日期:2006-05-15 00:00:00

  • Specification of axial identity in the mouse: role of the Hoxa-5 (Hox1.3) gene.

    abstract::Numerous lines of study have suggested that the Hox genes, encoding putative transcription factors, are key genes in the establishment of the body plan of the mammalian embryo. To examine the role of Hoxa-5 (Hox1.3) gene during development, we have used targeted mutagenesis in embryonic stem cells to produce a strain ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.7.11.2085

    authors: Jeannotte L,Lemieux M,Charron J,Poirier F,Robertson EJ

    更新日期:1993-11-01 00:00:00

  • Hedgehog signaling and the retina: insights into the mechanisms controlling the proliferative properties of neural precursors.

    abstract::Hedgehog signaling has been linked to cell proliferation in a variety of systems; however, its effects on the cell cycle have not been closely studied. In the vertebrate retina, Hedgehog's effects are controversial, with some reports emphasizing increased proliferation and others pointing to a role in cell cycle exit....

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.391106

    authors: Locker M,Agathocleous M,Amato MA,Parain K,Harris WA,Perron M

    更新日期:2006-11-01 00:00:00

  • Epigenetic effects on yeast transcription caused by mutations in an actin-related protein present in the nucleus.

    abstract::Gene inactivation can result when a delta element of the Ty1 transposon inserted into the yeast HIS4 promoter (his4-912delta) alters the transcription initiation site. Previous work has identified mutations that suppress this transcriptional defect by restoring the transcription start site to the native position, and ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.10.5.604

    authors: Jiang YW,Stillman DJ

    更新日期:1996-03-01 00:00:00

  • Human TAFII250 interacts with RAP74: implications for RNA polymerase II initiation.

    abstract::Accurate and regulated transcription by RNA polymerase II requires the assembly of an initiation complex involving multiple protein-DNA and protein-protein interactions. A key event is binding of TFIID, a complex consisting of TBP and associated factors (TAFs) to the template DNA. The TAF subunits of TFIID carry out d...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.9.22.2747

    authors: Ruppert S,Tjian R

    更新日期:1995-11-15 00:00:00

  • Involvement of the carboxyl terminus of vertebrate poly(A) polymerase in U1A autoregulation and in the coupling of splicing and polyadenylation.

    abstract::Interactions required for inhibition of poly(A) polymerase (PAP) by the U1 snRNP-specific U1A protein, a reaction whose function is to autoregulate U1A protein production, are examined. PAP inhibition requires a substrate RNA to which at least two molecules of U1A protein can bind tightly, but we demonstrate that the ...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.11.6.761

    authors: Gunderson SI,Vagner S,Polycarpou-Schwarz M,Mattaj IW

    更新日期:1997-03-15 00:00:00

  • APC sets the Wnt tone necessary for cerebral cortical progenitor development.

    abstract::Adenomatous polyposis coli (APC) regulates the activity of β-catenin, an integral component of Wnt signaling. However, the selective role of the APC-β-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated β-catenin signaling in cortical p...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.302679.117

    authors: Nakagawa N,Li J,Yabuno-Nakagawa K,Eom TY,Cowles M,Mapp T,Taylor R,Anton ES

    更新日期:2017-08-15 00:00:00

  • Mouse TU tagging: a chemical/genetic intersectional method for purifying cell type-specific nascent RNA.

    abstract::Transcriptional profiling is a powerful approach for understanding development and disease. Current cell type-specific RNA purification methods have limitations, including cell dissociation trauma or inability to identify all RNA species. Here, we describe "mouse thiouracil (TU) tagging," a genetic and chemical inters...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.205278.112

    authors: Gay L,Miller MR,Ventura PB,Devasthali V,Vue Z,Thompson HL,Temple S,Zong H,Cleary MD,Stankunas K,Doe CQ

    更新日期:2013-01-01 00:00:00

  • Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis.

    abstract::DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.260174.115

    authors: Rasmussen KD,Jia G,Johansen JV,Pedersen MT,Rapin N,Bagger FO,Porse BT,Bernard OA,Christensen J,Helin K

    更新日期:2015-05-01 00:00:00

  • SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay.

    abstract::Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that detects and degrades mRNAs containing premature stop codons (PTCs). In vertebrates, PTCs trigger efficient NMD when located upstream of an exon junction complex (EJC). Degradation of PTC-containing mRNAs requires the endonucleolytic activity of SMG...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.604610

    authors: Kashima I,Jonas S,Jayachandran U,Buchwald G,Conti E,Lupas AN,Izaurralde E

    更新日期:2010-11-01 00:00:00

  • A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway.

    abstract::Binding of microRNA (miRNA) to mRNA within the RNA-induced silencing complex (RISC) leads to either translational inhibition or to destruction of the target mRNA. Both of these functions are executed by Argonaute 2 (Ago2). Using hematopoiesis in mice as a model system to study the physiological function of Ago2 in viv...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1565607

    authors: O'Carroll D,Mecklenbrauker I,Das PP,Santana A,Koenig U,Enright AJ,Miska EA,Tarakhovsky A

    更新日期:2007-08-15 00:00:00

  • Bacterial promoter architecture: subsite structure of UP elements and interactions with the carboxy-terminal domain of the RNA polymerase alpha subunit.

    abstract::We demonstrate here that the previously described bacterial promoter upstream element (UP element) consists of two distinct subsites, each of which, by itself, can bind the RNA polymerase holoenzyme alpha subunit carboxy-terminal domain (RNAP alphaCTD) and stimulate transcription. Using binding-site-selection experime...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.13.16.2134

    authors: Estrem ST,Ross W,Gaal T,Chen ZW,Niu W,Ebright RH,Gourse RL

    更新日期:1999-08-15 00:00:00

  • Raf-induced MMP9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vivo.

    abstract::Organization into polarized three-dimensional structures defines whether epithelial cells are normal or malignant. In a model of morphogenesis, we show that inhibiting key signaling pathways in human breast cancer cells leads to "phenotypic reversion" of the malignant cells. Using architecture as an endpoint, we repor...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1990410

    authors: Beliveau A,Mott JD,Lo A,Chen EI,Koller AA,Yaswen P,Muschler J,Bissell MJ

    更新日期:2010-12-15 00:00:00

  • Maternal-biased H3K27me3 correlates with paternal-specific gene expression in the human morula.

    abstract::Genomic imprinting is an epigenetic mechanism by which genes are expressed in a parental origin-dependent manner. We recently discovered that, like DNA methylation, oocyte-inherited H3K27me3 can also serve as an imprinting mark in mouse preimplantation embryos. In this study, we found H3K27me3 is strongly biased towar...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.323105.118

    authors: Zhang W,Chen Z,Yin Q,Zhang D,Racowsky C,Zhang Y

    更新日期:2019-04-01 00:00:00

  • A 5' RNA element promotes dengue virus RNA synthesis on a circular genome.

    abstract::The mechanisms of RNA replication of plus-strand RNA viruses are still unclear. Here, we identified the first promoter element for RNA synthesis described in a flavivirus. Using dengue virus as a model, we found that the viral RdRp discriminates the viral RNA by specific recognition of a 5' element named SLA. We demon...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1444206

    authors: Filomatori CV,Lodeiro MF,Alvarez DE,Samsa MM,Pietrasanta L,Gamarnik AV

    更新日期:2006-08-15 00:00:00

  • A single Hox locus in Drosophila produces functional microRNAs from opposite DNA strands.

    abstract::MicroRNAs (miRNAs) are approximately 22-nucleotide RNAs that are processed from characteristic precursor hairpins and pair to sites in messages of protein-coding genes to direct post-transcriptional repression. Here, we report that the miRNA iab-4 locus in the Drosophila Hox cluster is transcribed convergently from bo...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.1613108

    authors: Stark A,Bushati N,Jan CH,Kheradpour P,Hodges E,Brennecke J,Bartel DP,Cohen SM,Kellis M

    更新日期:2008-01-01 00:00:00

  • Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.

    abstract::Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insig...

    journal_title:Genes & development

    pub_type: 杂志文章,评审

    doi:10.1101/gad.2021311

    authors: Polo SE,Jackson SP

    更新日期:2011-03-01 00:00:00

  • Genomic imprinting of Xist by maternal H3K27me3.

    abstract::Maternal imprinting at the Xist gene is essential to achieve paternal allele-specific imprinted X-chromosome inactivation (XCI) in female mammals. However, the mechanism underlying Xist imprinting is unclear. Here we show that the Xist locus is coated with a broad H3K27me3 domain that is established during oocyte grow...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.304113.117

    authors: Inoue A,Jiang L,Lu F,Zhang Y

    更新日期:2017-10-01 00:00:00

  • Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway.

    abstract::The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs). Seven genes (smg-1-7, for suppressor with morphological effect on genitalia) that are essential for NMD were originally identified in the nematode Caenorhabditis elegans, and orthologs of these gene...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.417707

    authors: Longman D,Plasterk RH,Johnstone IL,Cáceres JF

    更新日期:2007-05-01 00:00:00

  • Developmentally regulated fetal thymic and extrathymic T-cell receptor gamma delta gene expression.

    abstract::The gamma delta T-cell receptor (TCR) is the first TCR to be expressed in ontogeny in all vertebrates in which it has been examined thoroughly. Murine gamma delta cell-surface protein is detected by the fourteenth day of gestation. In this work, the activation of gamma delta RNA has been studied. Data indicate that th...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.4.8.1304

    authors: Carding SR,Kyes S,Jenkinson EJ,Kingston R,Bottomly K,Owen JJ,Hayday AC

    更新日期:1990-08-01 00:00:00

  • Foxp1 regulation of neonatal vocalizations via cortical development.

    abstract::The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 ar...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.305037.117

    authors: Usui N,Araujo DJ,Kulkarni A,Co M,Ellegood J,Harper M,Toriumi K,Lerch JP,Konopka G

    更新日期:2017-10-15 00:00:00

  • Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways.

    abstract::Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by impaired function of the neurofibromin RAS regulator. Using a combination of Nf1 genetically engineered mice and pharmacological/genetic inhibition approaches, we report that neurofibromin differentially controls neural stem cell (NSC) pr...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.261677.115

    authors: Chen YH,Gianino SM,Gutmann DH

    更新日期:2015-08-15 00:00:00

  • Position effect variegation in Drosophila is associated with an altered chromatin structure.

    abstract::A euchromatic gene placed in the vicinity of heterochromatin by a chromosomal rearrangement generally exhibits position effect variegation (PEV), a clonally inherited pattern showing gene expression in some somatic cells but not in others. The mechanism responsible for this loss of gene expression is investigated here...

    journal_title:Genes & development

    pub_type: 杂志文章

    doi:10.1101/gad.9.10.1263

    authors: Wallrath LL,Elgin SC

    更新日期:1995-05-15 00:00:00