Andrew P McMahon

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (322)3544.6 Total impact

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    ABSTRACT: Sonic hedgehog (Shh) signaling patterns the vertebrate spinal cord by activating a group of transcriptional repressors in distinct neural progenitors of somatic motor neuron and interneuron subtypes. To identify the action of this network, we performed a genome-wide analysis of the regulatory actions of three key ventral determinants in mammalian neural tube patterning: Nkx2.2, Nkx6.1 and Olig2. Previous studies have demonstrated that each factor acts predominantly as a transcriptional repressor, at least in part, to inhibit alternative progenitor fate choices. Here, we reveal broad and direct repression of multiple alternative fates as a general mechanism of repressor action. Additionally, the repressor network targets multiple Shh signaling components providing negative feedback to ongoing Shh signaling. Analysis of chromatin organization around Nkx2.2, Nkx6.1 and Olig2 bound regions, together with co-analysis of engagement of the transcriptional activator Sox2, indicate that repressors bind to, and likely modulate the action of, neural enhancers. Together, the data suggest a model for neural progenitor specification downstream of Shh signaling wherein Nkx2.2 and Olig2 direct repression of alternative neural progenitor fate determinants, an action augmented by the overlapping activity of Nkx6.1 in each cell type. Integration of repressor and activator inputs, notably activator inputs mediated by Sox2, is likely a key mechanism in achieving cell type-specific transcriptional outcomes in mammalian neural progenitor fate specification. © 2015. Published by The Company of Biologists Ltd.
    Development 08/2015; DOI:10.1242/dev.124636 · 6.27 Impact Factor
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    ABSTRACT: After acute kidney injury (AKI), surviving cells within the nephron proliferate and repair. We identify Sox9 as an acute epithelial stress response in renal regeneration. Translational profiling after AKI revealed a rapid upregulation of Sox9 within proximal tubule (PT) cells, the nephron cell type most vulnerable to AKI. Descendants of Sox9(+) cells generate the bulk of the nephron during development and regenerate functional PT epithelium after AKI-induced reactivation of Sox9 after renal injury. After restoration of renal function post-AKI, persistent Sox9 expression highlights regions of unresolved damage within injured nephrons. Inactivation of Sox9 in PT cells pre-injury indicates that Sox9 is required for the normal course of post-AKI recovery. These findings link Sox9 to cell intrinsic mechanisms regulating development and repair of the mammalian nephron. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; DOI:10.1016/j.celrep.2015.07.034 · 8.36 Impact Factor
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    Shinsuke Ohba · Xinjun He · Hironori Hojo · Andrew P McMahon
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    ABSTRACT: Sox9 encodes an essential transcriptional regulator of chondrocyte specification and differentiation. When Sox9 nuclear activity was compared with markers of chromatin organization and transcriptional activity in primary chondrocytes, we identified two distinct categories of target association. Class I sites cluster around the transcriptional start sites of highly expressed genes with no chondrocyte-specific signature. Here, Sox9 association reflects protein-protein association with basal transcriptional components. Class II sites highlight evolutionarily conserved active enhancers that direct chondrocyte-related gene activity through the direct binding of Sox9 dimer complexes to DNA. Sox9 binds through sites with sub-optimal binding affinity; the number and grouping of enhancers into super-enhancer clusters likely determines the levels of target gene expression. Interestingly, comparison of Sox9 action in distinct chondrocyte lineages points to similar regulatory strategies. In addition to providing insights into Sox family action, our comprehensive identification of the chondrocyte regulatory genome will facilitate the study of skeletal development and human disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 29. DOI:10.1016/j.celrep.2015.06.013 · 8.36 Impact Factor
  • Lori L. O’Brien · Andrew P. McMahon
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    ABSTRACT: The functional unit of the mammalian metanephric kidney is the nephron: a complex tubular structure dedicated to blood filtration and maintenance of several important physiological functions. Nephrons are assembled from a nephron-restricted pool of mesenchymal progenitors over an extensive developmental period that is completed prior to (human), or shortly after (mouse), birth. An appropriate balance in the expansion and commitment of nephron progenitors to nephron formation is essential for normal kidney function. Too few nephrons increases risk of kidney disease later in life while the failure of normal progenitor differentiation in Wilm's tumor patients leads to massive growth of a nephroblast population often necessitating surgical removal of the kidney. An inductive process within the metanephric mesenchyme leads to formation of a pretubular aggregate which transitions into an epithelial renal vesicle: the precursor for nephron assembly. Growth, morphogenesis and patterning transform this simple cyst-like structure into a highly elongated mature nephron with distinct cell types positioned along a proximal (glomerular) to distal (connecting segment) axis of functional organization. This review discusses our current understanding of the specification, maintenance and commitment of nephron progenitors, and the regulatory processes that transform the renal vesicle into a nephron.
    Seminars in Cell and Developmental Biology 12/2014; 36. DOI:10.1016/j.semcdb.2014.08.014 · 5.97 Impact Factor
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    ABSTRACT: Hedgehog signaling controls pattern formation in many vertebrate tissues. The downstream effectors of the pathway are the bifunctional Gli transcription factors, which, depending on hedgehog concentration, act as either transcriptional activators or repressors. Quantitatively understanding the interplay between Gli activator and repressor forms for patterning complex tissues is an open challenge. Here, we describe a reductionist mathematical model for how Gli activators and repressors are integrated in space and time to regulate transcriptional outputs of hedgehog signaling, using the pathway readouts Gli1 and Ptch1 as a model system. Spatially resolved measurements of absolute transcript numbers for these genes allow us to infer spatiotemporal variations of Gli activator and repressor levels. We validate our model by successfully predicting expression changes of Gli1 and Ptch1 in mutants at different developmental stages and in different tissues. Our results provide a starting point for understanding gene regulation by bifunctional transcription factors during mammalian development. Copyright © 2014 Elsevier Inc. All rights reserved.
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    ABSTRACT: The mammalian kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic functional unit of the kidney. However, the cellular mechanisms establishing stromal tissues are less clear. We demonstrate that the Foxd1-expressing cortical stroma represents a distinct multipotent self-renewing progenitor population that gives rise to stromal tissues of the interstitium, mesangium, and pericytes throughout kidney organogenesis. Fate map analysis of Foxd1-expressing cells demonstrates that a small subset of these cells contributes to Six2-expressing cells at the early stage of kidney outgrowth. Thereafter, there appears to be a strict nephron and stromal lineage boundary derived from Six2-expressing and Foxd1-expressing cell types, respectively. Taken together, our observations suggest that distinct multipotent self-renewing progenitor populations coordinate cellular differentiation of the nephron epithelium and renal stroma during mammalian kidney organogenesis.
    Stem Cell Reports 10/2014; 3(4). DOI:10.1016/j.stemcr.2014.08.008 · 5.64 Impact Factor
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    ABSTRACT: The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo. GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro. This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5, and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation.
    PLoS Genetics 10/2014; 10(10):e1004604. DOI:10.1371/journal.pgen.1004604 · 8.17 Impact Factor
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    ABSTRACT: The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes. Here, we have focused on the action of Stk11in the osteoblast lineage through osteoblast specific-removal of Stk11 activity. In the mouse model system, specification and primary organization of the neonatal boney skeleton is independent of Stk11. However, histological, molecular and micro-CT analysis revealed a marked perturbation of normal bone development evident in the immediate post-natal period. Cortical bone was unusually porous displaying a high rate of turnover with new trabeculae forming in the endosteal space. Trabecular bone also showed enhanced turnover and marked increase in the density of trabeculae and number of osteoclasts. Though mutants showed an expansion of bone volume and trabecular number their bone matrix comprised large amounts of osteoid and irregularly deposited woven bone highlighted by diffuse fluorochrome labeling. Additionally, we observed an increase in fibroblast-like cells associated with trabecular bone in Stk11 mutants. Stk11 down-regulates mTORC1 activity through control of upstream modulators of the AMP kinase family: an increase in the levels of the phosphorylated ribosomal protein S6, a target of mTORC1-mediated kinase activity, on osteoblast removal of Stk11 suggests deregulated mTORC1 activity contributes to the osteoblast phenotype. These data demonstrate Stk11 activity within osteoblasts is critical for the development of normally structured bone regulating directly the number and coordinated actions of osteoblasts, and indirectly osteoclast number.
    Bone 09/2014; 69. DOI:10.1016/j.bone.2014.09.010 · 4.46 Impact Factor
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    ABSTRACT: The large spectrum of limb morphologies reflects the wide evolutionary diversification of the basic pentadactyl pattern in tetrapods. In even-toed ungulates (artiodactyls, including cattle), limbs are adapted for running as a consequence of progressive reduction of their distal skeleton to symmetrical and elongated middle digits with hoofed phalanges. Here we analyse bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded SHH signalling during bovine handplate development. Our study provides a molecular explanation for the loss of digit asymmetry in bovine limb buds and suggests that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs.
    Nature 07/2014; 511(7507):46-51. DOI:10.1038/nature13289 · 42.35 Impact Factor
  • Sanjeev Kumar · Jing Liu · Andrew P McMahon
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    ABSTRACT: The mammalian kidney has an intrinsic ability to repair after significant injury. However, this process is inefficient: patients are at high risk for the loss of kidney function in later life. No therapy exists to treat established acute kidney injury (AKI) per se: strategies to promote endogenous repair processes and retard associated fibrosis are a high priority. Whole-organ gene expression profiling has been used to identify repair responses initiated with AKI, and factors that may promote the transition from AKI to chronic kidney disease. Transcriptional profiling has shown molecular markers and potential regulatory pathways of renal repair. Activation of a few key developmental pathways has been reported during repair. Whether these are comparable networks with similar target genes with those in earlier nephrogenesis remains unclear. Altered microRNA profiles, persistent tubular injury responses, and distinct late inflammatory responses highlight continuing kidney pathology. Additional insights into injury and repair processes will be gained by study of the repair transcriptome and cell-specific translatome using high-resolution technologies such as RNA sequencing and translational profiling tailored to specific cellular compartments within the kidney. An enhanced understanding holds promise for both the identification of novel therapeutic targets and biomarker-based evaluation of the damage-repair process.
    Seminars in Nephrology 07/2014; 34(4):404-417. DOI:10.1016/j.semnephrol.2014.06.007 · 2.94 Impact Factor
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    ABSTRACT: We previously described a mesenchymal stem cell (MSC)-like population within the adult mouse kidney that displays long-term colony-forming efficiency, clonogenicity, immunosuppression, and panmesodermal potential. Although phenotypically similar to bone marrow (BM)-MSCs, kidney MSC-like cells display a distinct expression profile. FACS sorting from Hoxb7/enhanced green fluorescent protein (GFP) mice identified the collecting duct as a source of kidney MSC-like cells, with these cells undergoing an epithelial-to-mesenchymal transition to form clonogenic, long-term, self-renewing MSC-like cells. Notably, after extensive passage, kidney MSC-like cells selectively integrated into the aquaporin 2-positive medullary collecting duct when microinjected into the kidneys of neonatal mice. No epithelial integration was observed after injection of BM-MSCs. Indeed, kidney MSC-like cells retained a capacity to form epithelial structures in vitro and in vivo, and conditioned media from these cells supported epithelial repair in vitro. To investigate the origin of kidney MSC-like cells, we further examined Hoxb7(+) fractions within the kidney across postnatal development, identifying a neonatal interstitial GFP(lo) (Hoxb7(lo)) population displaying an expression profile intermediate between epithelium and interstitium. Temporal analyses with Wnt4(GCE/+):R26(tdTomato/+) mice revealed evidence for the intercalation of a Wnt4-expressing interstitial population into the neonatal collecting duct, suggesting that such intercalation may represent a normal developmental mechanism giving rise to a distinct collecting duct subpopulation. These results extend previous observations of papillary stem cell activity and collecting duct plasticity and imply a role for such cells in collecting duct formation and, possibly, repair.
    Journal of the American Society of Nephrology 06/2014; 26(1). DOI:10.1681/ASN.2013050517 · 9.47 Impact Factor
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    ABSTRACT: Acute kidney injury (AKI) promotes an abrupt loss of kidney function that results in substantial morbidity and mortality. Considerable effort has gone toward identification of diagnostic biomarkers and analysis of AKI-associated molecular events; however, most studies have adopted organ-wide approaches and have not elucidated the interplay among different cell types involved in AKI pathophysiology. To better characterize AKI-associated molecular and cellular events, we developed a mouse line that enables the identification of translational profiles in specific cell types. This strategy relies on CRE recombinase-dependent activation of an EGFP-tagged L10a ribosomal protein subunit, which allows translating ribosome affinity purification (TRAP) of mRNA populations in CRE-expressing cells. Combining this mouse line with cell type-specific CRE-driver lines, we identified distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Twenty-four hours following IRI, distinct translational signatures were identified in the nephron, kidney interstitial cell populations, vascular endothelium, and macrophages/monocytes. Furthermore, TRAP captured known IRI-associated markers, validating this approach. Biological function annotation, canonical pathway analysis, and in situ analysis of identified response genes provided insight into cell-specific injury signatures. Our study provides a deep, cell-based view of early injury-associated molecular events in AKI and documents a versatile, genetic tool to monitor cell-specific and temporal-specific biological processes in disease modeling.
    The Journal of clinical investigation 05/2014; 124(5):2288. DOI:10.1172/JCI76261 · 13.77 Impact Factor
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    ABSTRACT: Although kidneys of equal size can vary 10-fold in nephron number at birth, discovering what regulates such variation has been hampered by a lack of quantitative parameters defining kidney development. Here we report a comprehensive, quantitative, multiscale analysis of mammalian kidney development in which we measure changes in cell number, compartment volumes, and cellular dynamics across the entirety of organogenesis, focusing on two key nephrogenic progenitor populations: the ureteric epithelium and the cap mesenchyme. In doing so, we describe a discontinuous developmental program governed by dynamic changes in interactions between these key cellular populations occurring within a previously unappreciated structurally stereotypic organ architecture. We also illustrate the application of this approach to the detection of a subtle mutant phenotype. This baseline program of kidney morphogenesis provides a framework for assessing genetic and environmental developmental perturbation and will serve as a gold standard for the analysis of other organs.
    Developmental Cell 04/2014; 29(2):188-202. DOI:10.1016/j.devcel.2014.02.017 · 10.37 Impact Factor
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    ABSTRACT: Myofibroblasts secrete matrix during chronic injury, and their ablation ameliorates fibrosis. Development of new biomarkers and therapies for CKD will be aided by a detailed analysis of myofibroblast gene expression during the early stages of fibrosis. However, dissociating myofibroblasts from fibrotic kidney is challenging. We therefore adapted translational ribosome affinity purification (TRAP) to isolate and profile mRNA from myofibroblasts and their precursors during kidney fibrosis. We generated and characterized a transgenic mouse expressing an enhanced green fluorescent protein (eGFP)-tagged L10a ribosomal subunit protein under control of the collagen1α1 promoter. We developed a one-step procedure for isolation of polysomal RNA from collagen1α1-eGFPL10a mice subject to unilateral ureteral obstruction and analyzed and validated the resulting transcriptional profiles. Pathway analysis revealed strong gene signatures for cell proliferation, migration, and shape change. Numerous novel genes and candidate biomarkers were upregulated during fibrosis, specifically in myofibroblasts, and we validated these results by quantitative PCR, in situ, and Western blot analysis. This study provides a comprehensive analysis of early myofibroblast gene expression during kidney fibrosis and introduces a new technique for cell-specific polysomal mRNA isolation in kidney injury models that is suited for RNA-sequencing technologies.
    Journal of the American Society of Nephrology 03/2014; 25(9). DOI:10.1681/ASN.2013101143 · 9.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute kidney injury (AKI) promotes an abrupt loss of kidney function that results in substantial morbidity and mortality. Considerable effort has gone toward identification of diagnostic biomarkers and analysis of AKI-associated molecular events; however, most studies have adopted organ-wide approaches and have not elucidated the interplay among different cell types involved in AKI pathophysiology. To better characterize AKI-associated molecular and cellular events, we developed a mouse line that enables the identification of translational profiles in specific cell types. This strategy relies on CRE recombinase-dependent activation of an EGFP-tagged L10a ribosomal protein subunit, which allows translating ribosome affinity purification (TRAP) of mRNA populations in CRE-expressing cells. Combining this mouse line with cell type-specific CRE-driver lines, we identified distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Twenty-four hours following IRI, distinct translational
  • S. Kumar · J. Liu · A.P. McMahon
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian kidney has an intrinsic ability to repair after significant injury. However, this process is inefficient: patients are at high risk for the loss of kidney function in later life. No therapy exists to treat established acute kidney injury (AKI) per se: strategies to promote endogenous repair processes, and retard associated fibrosis are a high priority. Whole-organ gene expression profiling has been used to identify repair responses initiated on AKI, and factors that may promote the transition from AKI to chronic kidney disease (CKD). Transcriptional profiling has revealed molecular markers and potential regulatory pathways of renal repair. Activation of a few key developmental pathways has been reported during repair. Whether these are comparable networks with similar target genes to those in earlier nephrogenesis remains unclear. Altered microRNA profiles, persistent tubular injury responses, and distinct late inflammatory responses highlight continuing kidney pathology. Additional insights into injury and repair processes will be gained by study of the repair transcriptome and cell-specific translatome utilizing high-resolution technologies such as RNA sequencing and translational profiling tailored to specific cellular compartments within the kidney. An enhanced understanding holds promise for both the identification of novel therapeutic targets and biomarker-based evaluation of the damage-repair process.
    Seminars in Nephrology 01/2014; · 2.94 Impact Factor
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    ABSTRACT: The Kidney Research National Dialogue represents a novel effort by the National Institute of Diabetes and Digestive and Kidney Diseases to solicit and prioritize research objectives from the renal research and clinical communities. The present commentary highlights selected scientific opportunities specific to the study of renal development, physiology, and cell biology. Describing such fundamental kidney biology serves as a necessary foundation for translational and clinical studies that will advance disease care and prevention. It is intended that these objectives foster and focus scientific efforts in these areas in the coming decade and beyond.
    Clinical Journal of the American Society of Nephrology 12/2013; 9(4). DOI:10.2215/CJN.10851013 · 5.25 Impact Factor
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    Yu Wang · Andrew P McMahon
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    ABSTRACT: Oxysterols modulate the Hedgehog signalling pathway by binding a novel site on the membrane protein Smoothened, which may offer new options for the treatment of cancers linked to this pathway.
    eLife Sciences 12/2013; 2:e01680. DOI:10.7554/eLife.01680 · 8.52 Impact Factor
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    ABSTRACT: Canonical Wnt signaling supports the pluripotency of embryonic stem cells (ESCs) but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for ESC culture suggests MEK/ERK signaling and canonical Wnt signaling combine to promote ESC differentiation.
    Stem Cells 12/2013; 31(12). DOI:10.1002/stem.1371 · 7.70 Impact Factor
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    M Rajurkar · H Huang · J L Cotton · J K Brooks · J Sicklick · A P McMahon · J Mao
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    ABSTRACT: Dysregulation of the Hedgehog (Hh)-Gli signaling pathway is implicated in a variety of human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB) and embryonal rhabdhomyosarcoma (eRMS), three principle tumors associated with human Gorlin syndrome. However, the cells of origin of these tumors, including eRMS, remain poorly understood. In this study, we explore the cell populations that give rise to Hh-related tumors by specifically activating Smoothened (Smo) in both Hh-producing and -responsive cell lineages in postnatal mice. Interestingly, we find that unlike BCC and MB, eRMS originates from the stem/progenitor populations that do not normally receive active Hh signaling. Furthermore, we find that the myogenic lineage in postnatal mice is largely Hh quiescent and that Pax7-expressing muscle satellite cells are not able to give rise to eRMS upon Smo or Gli1/2 overactivation in vivo, suggesting that Hh-induced skeletal muscle eRMS arises from Hh/Gli quiescent non-myogenic cells. In addition, using the Gli1 null allele and a Gli3 repressor allele, we reveal a specific genetic requirement for Gli proteins in Hh-induced eRMS formation and provide molecular evidence for the involvement of Sox4/11 in eRMS cell survival and differentiation.Oncogene advance online publication, 25 November 2013; doi:10.1038/onc.2013.480.
    Oncogene 11/2013; 33(46). DOI:10.1038/onc.2013.480 · 8.56 Impact Factor

Publication Stats

52k Citations
3,544.60 Total Impact Points

Top Journals

Institutions

  • 2013–2014
    • University of California, Los Angeles
      Los Ángeles, California, United States
    • Brigham and Women's Hospital
      • Division of Renal Medicine
      Boston, Massachusetts, United States
  • 2012–2014
    • University of Southern California
      • • Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC
      • • Keck School of Medicine
      Los Angeles, California, United States
    • University of Queensland 
      • Institute for Molecular Bioscience
      Brisbane, Queensland, Australia
  • 1994–2014
    • Harvard University
      • • Department of Molecular and Cell Biology
      • • Department of Developmental Biology
      Cambridge, Massachusetts, United States
  • 2008
    • Neural Stem Cell Institute
      Rensselaer, New York, United States
    • The University of Edinburgh
      • Centre for Integrative Physiology
      Edinburgh, Scotland, United Kingdom
  • 1997–2008
    • Harvard Medical School
      • Department of Genetics
      Boston, MA, United States
    • Max Planck Society
      München, Bavaria, Germany
  • 2003
    • CUNY Graduate Center
      New York, New York, United States
    • University of Ottawa
      • Department of Biochemistry, Microbiology and Immunology
      Ottawa, Ontario, Canada
  • 2002
    • Wesleyan University
      • Department of Biology
      मिडलटाउन, Connecticut, United States
  • 2001
    • University of Colorado at Boulder
      Boulder, Colorado, United States
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 2000
    • Molecular and Cellular Biology Program
      • Department of Molecular and Cellular Biology
      Seattle, Washington, United States
    • University of Oulu
      • Department of Biochemistry
      Uleoborg, Northern Ostrobothnia, Finland
  • 1999
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1989–1995
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
  • 1987–1989
    • MRC National Institute for Medical Research
      • Division of Developmental Neurobiology
      Londinium, England, United Kingdom