Smooth Muscle Tension Induces Invasive Remodeling of the Zebrafish Intestine
Publication Date
September 04, 2012
Journal
PLOS Biology
Authors
Christoph Seiler, Gangarao Davuluri, Joshua Abrams, Fitzroy J. Byfield, et al
Volume
10
Issue
9
Pages
e1001386
DOI
https://dx.plos.org/10.1371/journal.pbio.1001386
Publisher URL
http://journals.plos.org/plosbiology/article?id=10.1371%2Fjournal.pbio.1001386
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/22973180
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433428
Europe PMC
http://europepmc.org/abstract/MED/22973180
Web of Science
000309520100001
Scopus
84866708698
Mendeley
http://www.mendeley.com/research/smooth-muscle-tension-induces-invasive-remodeling-zebrafish-intestine
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Mendeley | Further Information

{"title"=>"Smooth Muscle Tension Induces Invasive Remodeling of the Zebrafish Intestine", "type"=>"journal", "authors"=>[{"first_name"=>"Christoph", "last_name"=>"Seiler", "scopus_author_id"=>"36153661900"}, {"first_name"=>"Gangarao", "last_name"=>"Davuluri", "scopus_author_id"=>"25635569600"}, {"first_name"=>"Joshua", "last_name"=>"Abrams", "scopus_author_id"=>"36778630600"}, {"first_name"=>"Fitzroy J.", "last_name"=>"Byfield", "scopus_author_id"=>"55915704500"}, {"first_name"=>"Paul A.", "last_name"=>"Janmey", "scopus_author_id"=>"7005414195"}, {"first_name"=>"Michael", "last_name"=>"Pack", "scopus_author_id"=>"7007055261"}], "year"=>2012, "source"=>"PLoS Biology", "identifiers"=>{"pui"=>"365720695", "isbn"=>"1545-7885", "issn"=>"15449173", "doi"=>"10.1371/journal.pbio.1001386", "scopus"=>"2-s2.0-84866708698", "pmid"=>"22973180", "sgr"=>"84866708698"}, "id"=>"4b320611-fbef-3d6a-93e1-4723e195e3bb", "abstract"=>"The signals that initiate cell invasion are not well understood, but there is increasing evidence that extracellular physical signals play an important role. Here we show that epithelial cell invasion in the intestine of zebrafish meltdown (mlt) mutants arises in response to unregulated contractile tone in the surrounding smooth muscle cell layer. Physical signaling in mlt drives formation of membrane protrusions within the epithelium that resemble invadopodia, matrix-degrading protrusions present in invasive cancer cells. Knockdown of Tks5, a Src substrate that is required for invadopodia formation in mammalian cells blocked formation of the protrusions and rescued invasion in mlt. Activation of Src-signaling induced invadopodia-like protrusions in wild type epithelial cells, however the cells did not migrate into the tissue stroma, thus indicating that the protrusions were required but not sufficient for invasion in this in vivo model. Transcriptional profiling experiments showed that genes responsive to reactive oxygen species (ROS) were upregulated in mlt larvae. ROS generators induced invadopodia-like protrusions and invasion in heterozygous mlt larvae but had no effect in wild type larvae. Co-activation of oncogenic Ras and Wnt signaling enhanced the responsiveness of mlt heterozygotes to the ROS generators. These findings present the first direct evidence that invadopodia play a role in tissue cell invasion in vivo. In addition, they identify an inducible physical signaling pathway sensitive to redox and oncogenic signaling that can drive this process.", "link"=>"http://www.mendeley.com/research/smooth-muscle-tension-induces-invasive-remodeling-zebrafish-intestine", "reader_count"=>45, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>10, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>3, "Student > Master"=>7, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>10, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>3, "Student > Master"=>7, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>29, "Medicine and Dentistry"=>1, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>1, "Social Sciences"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Neuroscience"=>{"Neuroscience"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>29}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>3}, "group_count"=>3}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/583416"], "description"=>"<p>(A, B) Lateral views of live, menadione treated 5 dpf <i>axin</i> mutant larvae that express mutant <i>KRAS</i> in the intestinal epithelium (<i>Kras-axin</i>). (A) Hypertrophy of the intestinal epithelium in a <i>Kras-axin</i> larva that is homozygous for the wildtype <i>myh11</i> allele (mlt +/+) larvae is unchanged by treatment with menadione. (B) Menadione treatment causes pronounced cystic expansion of the posterior intestinal epithelium of the <i>Kras-axin mlt</i> heterozygote (arrowheads) that resembles the homozygous <i>mlt</i> phenotype. Inset, immunolabeling of the basal lamina (laminin, green) and epithelium (cytokeratin, red) shows epithelial cell invasion through the basement membrane. (C–E) Histological cross-sections through the intestine of immunostained larvae show invasive cells in menadione treated <i>Kras-axin mlt</i> heterozygotes (arrowheads; D, E). Invasion is not detected in menadione-treated <i>Kras-axin mlt</i> larvae that are homozygous for the wildtype <i>myh11</i> allele (C).</p>", "links"=>[], "tags"=>["oncogenic", "signaling", "enhances", "heterozygotes", "oxidative"], "article_id"=>253904, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g011", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_oncogenic_signaling_enhances_sensitivity_of_mlt_heterozygotes_to_oxidative_stress_/253904", "title"=>"Activation of oncogenic signaling enhances sensitivity of <i>mlt</i> heterozygotes to oxidative stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 01:05:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/582679"], "description"=>"<p>Sagittal confocal images from time lapse movies (Movies S7 and S8) of transgenic WT (A–C) and <i>mlt</i> (D–H) larvae (anterior left) expressing fluorescent reporters. Intestinal epithelium (I) and pronephric duct (P) labeled red; intestinal smooth muscle labeled green. WT images beginning at 76 hpf show cycling of the contracted (A, C) and relaxed state (B); brackets depict intestinal diameter. (D–F) The <i>mlt</i> intestine at this stage shows progressive contraction that disrupts intestinal architecture. (G, H) Smooth muscle contraction is not detected in the <i>mlt</i> intestine at the onset of invasive remodeling (72 hpf). (I) Western blot showing premature phosphorylation of h-CaD (p-Cad) in 72 hpf <i>mlt</i> larvae, before the onset of smooth muscle contraction (ratio WT:<i>mlt</i> = 0.17/1, relative to Actin loading control; in four independent experiments, the ratio averaged 0.13/1; <i>p</i> = 0.002). Phospho-h-CaD is present at the onset of contraction in WT at 78 hpf and is comparable to <i>mlt</i> (ratio WT:<i>mlt</i> = 1.12/1, relative to Actin; no significant difference in four independent experiments). Levels of phospho-Myosin light chain (p-Mlc) are low at 72 hpf in both <i>mlt</i> and WT (ratio WT:<i>mlt</i> = 1.16/1, relative to Actin) and are increased when contractions occur at 78 hpf (ratio WT:<i>mlt</i> = 0.96/1, relative to Actin). There was no significant difference between WT and <i>mlt</i> at either time point in four independent experiments. Actin (beta-Actin), loading control.</p>", "links"=>[], "tags"=>["intestinal", "contraction"], "article_id"=>253179, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tonic_intestinal_smooth_muscle_contraction_in_mlt_mutants_/253179", "title"=>"Tonic intestinal smooth muscle contraction in <i>mlt</i> mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:52:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/581650"], "description"=>"<p>(A–C) Live images of wild type (WT) and <i>mlt</i> larvae. In WT (A) the posterior intestine forms a smooth cylindrical tube (box), whereas in <i>mlt</i> at 74 hpf the intestinal contour is irregular (B). Cystic expansion of the intestine is evident in 86 hpf <i>mlt</i> larvae (C). (D–H) Histological cross-sections through the posterior intestine of larvae immunostained for laminin (green) and cytokeratin (red). The WT intestine is comprised of a simple epithelial sheet consisting of a single layer of cells, whereas in <i>mlt</i> epithelial stratification (asterisks) and invasive cells that have breached the basement membrane are evident (E–G arrowheads). The initial invasive behavior is followed by expansive growth and loss of epithelial architecture (H).</p>", "links"=>[], "tags"=>["epithelial"], "article_id"=>252140, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Intestinal_epithelial_invasion_in_mlt_larvae_/252140", "title"=>"Intestinal epithelial invasion in <i>mlt</i> larvae.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:35:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/308019", "https://ndownloader.figshare.com/files/308127", "https://ndownloader.figshare.com/files/308192", "https://ndownloader.figshare.com/files/308253", "https://ndownloader.figshare.com/files/308340", "https://ndownloader.figshare.com/files/308421", "https://ndownloader.figshare.com/files/308491", "https://ndownloader.figshare.com/files/308550", "https://ndownloader.figshare.com/files/308614", "https://ndownloader.figshare.com/files/308681", "https://ndownloader.figshare.com/files/308722", "https://ndownloader.figshare.com/files/308771", "https://ndownloader.figshare.com/files/308855", "https://ndownloader.figshare.com/files/308921", "https://ndownloader.figshare.com/files/308995", "https://ndownloader.figshare.com/files/309061", "https://ndownloader.figshare.com/files/309134", "https://ndownloader.figshare.com/files/309201"], "description"=>"<div><p>The signals that initiate cell invasion are not well understood, but there is increasing evidence that extracellular physical signals play an important role. Here we show that epithelial cell invasion in the intestine of zebrafish <em>meltdown</em> (<em>mlt</em>) mutants arises in response to unregulated contractile tone in the surrounding smooth muscle cell layer. Physical signaling in <em>mlt</em> drives formation of membrane protrusions within the epithelium that resemble invadopodia, matrix-degrading protrusions present in invasive cancer cells. Knockdown of Tks5, a Src substrate that is required for invadopodia formation in mammalian cells blocked formation of the protrusions and rescued invasion in <em>mlt</em>. Activation of Src-signaling induced invadopodia-like protrusions in wild type epithelial cells, however the cells did not migrate into the tissue stroma, thus indicating that the protrusions were required but not sufficient for invasion in this in vivo model. Transcriptional profiling experiments showed that genes responsive to reactive oxygen species (ROS) were upregulated in <em>mlt</em> larvae. ROS generators induced invadopodia-like protrusions and invasion in heterozygous <em>mlt</em> larvae but had no effect in wild type larvae. Co-activation of oncogenic Ras and Wnt signaling enhanced the responsiveness of <em>mlt</em> heterozygotes to the ROS generators. These findings present the first direct evidence that invadopodia play a role in tissue cell invasion in vivo. In addition, they identify an inducible physical signaling pathway sensitive to redox and oncogenic signaling that can drive this process.</p> </div>", "links"=>[], "tags"=>["induces", "invasive", "remodeling", "zebrafish", "intestine"], "article_id"=>120775, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1001386.s001", "https://dx.doi.org/10.1371/journal.pbio.1001386.s002", "https://dx.doi.org/10.1371/journal.pbio.1001386.s003", "https://dx.doi.org/10.1371/journal.pbio.1001386.s004", "https://dx.doi.org/10.1371/journal.pbio.1001386.s005", "https://dx.doi.org/10.1371/journal.pbio.1001386.s006", "https://dx.doi.org/10.1371/journal.pbio.1001386.s007", "https://dx.doi.org/10.1371/journal.pbio.1001386.s008", "https://dx.doi.org/10.1371/journal.pbio.1001386.s009", "https://dx.doi.org/10.1371/journal.pbio.1001386.s010", "https://dx.doi.org/10.1371/journal.pbio.1001386.s011", "https://dx.doi.org/10.1371/journal.pbio.1001386.s012", "https://dx.doi.org/10.1371/journal.pbio.1001386.s013", "https://dx.doi.org/10.1371/journal.pbio.1001386.s014", "https://dx.doi.org/10.1371/journal.pbio.1001386.s015", "https://dx.doi.org/10.1371/journal.pbio.1001386.s016", "https://dx.doi.org/10.1371/journal.pbio.1001386.s017", "https://dx.doi.org/10.1371/journal.pbio.1001386.s018"], "stats"=>{"downloads"=>88, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Smooth_Muscle_Tension_Induces_Invasive_Remodeling_of_the_Zebrafish_Intestine/120775", "title"=>"Smooth Muscle Tension Induces Invasive Remodeling of the Zebrafish Intestine", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-09-04 00:12:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/582268"], "description"=>"<p>(A–D) Sagittal confocal scans through the intestine of 74 hpf wild type and <i>mlt</i> larvae that express Src-mCherry (red) and Lifeact-GFP (green) in the intestinal epithelium. (A) In WT, Src (red) is localized at the apical (ap) and lateral epithelial cell membrane. (B) In <i>mlt</i>, Src also localizes to sites of actin-rich (green) invadopodia-like protrusions (arrowheads B) arising from the basal epithelial cell membrane (ba). (C) Constitutively active Src (caSrc; red) localizes to invadopodia-like protrusions (green) in <i>mlt</i> (arrowheads). (D) caSrc induces formation of the protrusions in WT (arrowheads). (E) Histological cross-sections through the intestine of a 74 hpf wild type larva showing caSrc-rich protrusions (green) protruding through small degraded regions of the basal lamina (laminin immunostain, red). Additional examples are shown in high power images (E, E′, and E″).</p>", "links"=>[], "tags"=>["induces", "invadopodia-like", "protrusions", "intestine", "zebrafish"], "article_id"=>252757, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g004", "stats"=>{"downloads"=>3, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Src_induces_formation_of_invadopodia_like_protrusions_in_the_intestine_of_wild_type_zebrafish_larvae_/252757", "title"=>"Src induces formation of invadopodia-like protrusions in the intestine of wild type zebrafish larvae.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:45:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/582987"], "description"=>"<p>(A) Quantitative RT-PCR shows increased intestinal <i>gpx</i> expression in 74 hpf <i>mlt</i> homozygotes (<i>mlt</i> −/−) compared with WT (+/+) and <i>mlt</i> heterozygotes (<i>mlt +/</i>−) (** <i>p</i><.01). (A′) Quantitative RT-PCR shows intestinal <i>gpx</i> expression is increased in menadione treated homozygous WT larvae (+/+ mena) compared with untreated WT (contr). A much stronger response to menadione is seen in <i>mlt</i> heterozygotes (+/− mena) (*** <i>p</i><.001). (B) ROS production in intestinal epithelial cells of 76 hpf WT control larvae (contr) versus menadione treated homozygous WT and heterozygous <i>mlt</i> larvae (*** <i>p</i><.001). Bar graphs in (A) and (A′) show mean and standard deviation of three independent experiments. Bar graph in (B) shows mean of six larvae for each genotype; 15–25 cells per larva. (C–F) Histological cross-sections of larvae processed for fluorescent RNA in situ hybridization. Menadione induced <i>gpx</i> expression (red) in the epithelium but not smooth muscle (green) of heterozygous <i>mlt</i> larvae (F). This is comparable to the <i>gpx</i> expression pattern in control homozygous <i>mlt</i> larvae (D). (G) Western blot showing premature h-CaD phosphorylation (pCad) in dissected intestines from menadione treated heterozygotes but not homozygous WT larvae (lane 4 versus lane 3; ratio phospho-h-CaD WT:<i>mlt</i> = 0.02/1, relative to total h-CaD; CaD; in six experiments the ratio averaged 0.016/1; <i>p</i><.001). h-CaD is prematurely phosphorylated in intestines dissected from 74 hpf <i>mlt</i> homozygotes versus <i>mlt</i> heterozygotes (lane 1 versus lane 2). (H) Western blot showing h-CaD phosphorylation (pCad) in the menadione treated heterozygous intestines prior to dissociation (lane 2) but not after dissociation into free cell populations (lane 5). Phospho-h-CaD persists in dissociated cells from homozygous intestines (lane 3), but is not detected in control intestines dissected from <i>mlt</i> heterozygotes, before (lane 1) or after (lane 4) dissociation into free cell populations. No phopho-h-CaD was detected in any dissociated samples in three independent experiments. Loading control, phospho-Myosin light chain (pMlc).</p>", "links"=>[], "tags"=>["larvae", "sensitized", "oxidative"], "article_id"=>253475, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g008", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Heterozygous_mlt_larvae_are_sensitized_to_oxidative_stress_/253475", "title"=>"Heterozygous <i>mlt</i> larvae are sensitized to oxidative stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:57:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/582068"], "description"=>"<p>(A–C) Histological cross-sections through the posterior intestine of 74 hpf <i>mlt</i> mutant larvae immunostained with antibodies against GFP (green) (labeling Lifeact-GFP) and Cortactin (red). DAPI-stained nuclei, blue. Lifeact-GFP and Cortactin co-localize in actin rich basal membrane protrusions (arrowheads) and in the apical brush border (ap). (D–G) Sagittal confocal scans through the intestine of 74 hpf Lifeact-GFP transgenic wild type (WT) and <i>mlt</i> larvae. Lifeact-GFP binds actin in the apical brush border (ap) of WT (D) and <i>mlt</i> (E, F) epithelial cells, as well as basal (ba) invadopodia-like protrusions in <i>mlt</i> (E, F, arrows). In WT, the Mmp14a-mCherry fusion protein (red) is distributed throughout the epithelial cells. In <i>mlt</i>, Mmp14a-mCherry is preferentially localized to the basal region of the epithelial cells. (<i>n</i> = 33 WT and 33 <i>mlt</i> cells examined; 6 larvae each genotype). (G) Ratio of basal to apical Mmp14a-mCherry in WT versus <i>mlt</i> epithelial cells (error bars, standard deviation. * <i>p</i><.001). (H–I) Sagittal confocal scans through the intestines of 84 hpf Lifeact-GFP transgenic <i>mlt</i> larvae. Invadopodia (arrowheads I) and invasive cells (asterisks I) are present in the <i>mlt</i> larvae injected with a control morpholino (I), but are not detected in the larvae injected with the <i>tks5</i> morpholino (H).</p>", "links"=>[], "tags"=>["protrusions", "invadopodia"], "article_id"=>252560, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Actin_rich_protrusions_in_mlt_are_invadopodia_homologs_/252560", "title"=>"Actin rich protrusions in <i>mlt</i> are invadopodia homologs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:42:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/582835"], "description"=>"<p>(A–C) Lateral views of live 5 dpf larvae injected with Sma or control morpholino. (A) Sma knockdown has no effect on WT intestinal morphology. (B) Control morpholino injection in <i>mlt</i>. (C) Sma knockdown rescues invasion in <i>mlt</i>. Residual invasive cells persist in this Sma deficient <i>mlt</i> larva (arrowhead). (D–I) Histological cross-sections through the posterior intestine of 74 hpf WT and <i>mlt</i> larvae immunostained with anti-keratin (red) and anti-laminin (green) antibodies. (D) WT. (E, F) <i>mlt</i> larvae injected with control (E) and Sma (D, F) morpholinos. Invasive cells in <i>mlt</i> (arrowheads, E) are rescued by Sma knockdown. (G, H) Injection of a morpholino targeting the high molecular weight isoform of Caldesmon (cald) has no effect on WT intestinal morphology but induces invasion (arrowhead) and stratification (asterisk) in an <i>mlt</i> heterozygote. (I) Treatment of an <i>mlt</i> heterozygote with L-NAME causes invasion (arrowhead) and epithelial stratification (asterisk). (J) Force displacement measurements show identical compliance of intestines dissected from <i>mlt</i> and WT larvae before the phenotype develops at 70 hpf, and a modest increase in compliance at the outer surface of the intestine (<4 micron indentation) when invasion is present at 74 hpf. (K) Compliance is indicated by Young's modulus, which is proportional to the slope of the Force versus Tissue indentation curve.</p>", "links"=>[], "tags"=>["contraction", "drives", "epithelial"], "article_id"=>253326, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g007", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Smooth_muscle_contraction_drives_epithelial_invasion_but_does_not_alter_tissue_rigidity_/253326", "title"=>"Smooth muscle contraction drives epithelial invasion but does not alter tissue rigidity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:55:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/583122"], "description"=>"<p>(A–C) Lateral images of live WT (A), <i>mlt</i> homozygous (B), and <i>mlt</i> heterozygous larvae (C). The WT and <i>mlt</i> heterozygous larvae received 3 h of treatment with Menadione beginning at 73 hpf. Menadione treated heterozygote (C) larvae have an intestinal phenotype (arrowheads) resembling the untreated <i>mlt</i> homozygous larvae (B). (D–F) Corresponding histological cross-sections (representative of larvae in A, C) with intestinal epithelial cells labeled red (anti-keratin immunostain) and basement membrane in green (anti-laminin immunostain). Menadione causes epithelial cell invasion (arrows) and stratification (asterisks) in <i>mlt</i> heterozygous larvae (E, F) but does not affect epithelial architecture in the WT intestines (D). (G–I) Sagittal confocal scans through the intestine of WT and <i>mlt</i> heterozygotes treated with menadione. Both larvae express LifeAct-GFP in a subset of intestinal epithelial cells. Actin-rich invadopodia-like protrusions (green) are seen arising from the basal epithelial cell membrane of menadione treated heterozygous larvae (arrowheads, H, I). Actin is located nearly exclusively in the apical brush border of WT epithelial cells (G): Red -membrane mCherry; ba, basal epithelial cell border; ap, apical epithelial cell border.</p>", "links"=>[], "tags"=>["induces", "invasive", "remodeling", "heterozygous"], "article_id"=>253611, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g009", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Oxidative_stress_induces_invasive_remodeling_in_mlt_heterozygous_larvae_/253611", "title"=>"Oxidative stress induces invasive remodeling in <i>mlt</i> heterozygous larvae.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 01:00:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/581791"], "description"=>"<p><b>intestine.</b> (A, B) Full thickness 3-D rendering of sagittal confocal sections through the intestine of 78 hpf wild type (WT) (A) and <i>mlt</i> (B) larvae. Actin is labeled by transgenic Lifeact-GFP expression (green). (A) In WT, the majority of the label is present in the epithelial cell apical brush border (bracket). (B) In <i>mlt</i>, actin-rich invadopodia-like protrusions of the basal epithelial cell membrane are detected (arrows), in addition to brush border actin (bracket). (C) Time lapse analysis of protrusion development. Single sagittal confocal scans through the intestine of a <i>mlt</i> larva beginning at 74 hpf. Basal invadopodia-like protrusions (arrowheads) precede cell invasion, which is first detected at 135 min. Asterisks mark invasive cells at 270 min (see also B). (D–F) Histological cross-sections through the intestine of 74 hpf immunostained <i>mlt</i> larvae. Basement membrane is labeled red (laminin immunostain) and actin labeled green (GFP immunostain in Lifeact-GFP transgenics). Nuclei stained blue with DAPI. Actin rich protrusions in <i>mlt</i> co-localize with sites of basal lamina degradation (arrowheads and insets E, F). During progression of the phenotype epithelial cells invade the tissue stroma through degraded regions of the basal lamina (asterisks in F). ap, apical epithelial cell border; ba, basal cell epithelial cell border.</p>", "links"=>[], "tags"=>["protrusions", "invasive", "epithelial", "cells"], "article_id"=>252277, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g002", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Actin_rich_protrusions_in_invasive_epithelial_cells_of_the_mlt_/252277", "title"=>"Actin-rich protrusions in invasive epithelial cells of the <i>mlt</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:37:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/582508"], "description"=>"<p>(A–C) Lateral views of live 5 dpf WT (A) and <i>mlt</i> (B, C) larvae. Treatment with the Src-I1 inhibitor rescues invasion in <i>mlt</i> (C). The size of the intestinal epithelium in the treated <i>mlt</i> larva (C) is reduced compared with the untreated <i>mlt</i> larva (B). (D–G) Histological cross-sections of 4 dpf WT (D) and <i>mlt</i> (E–G) <i>Tg(miR194:Lifeact-GFP)</i> larvae immunostained with antibodies against laminin (red) and GFP (green). Nuclei stained blue with DAPI. Arrows point to invadopodia-like protrusions arising from the basal epithelial cell membrane of Src-I1 treated <i>mlt</i> larvae (F, G). Pronounced invasion with distortion of intestinal architecture is evident in the untreated <i>mlt</i> larva (E). Note that invasion is markedly reduced in the Src-I1 treated <i>mlt</i> larvae despite the presence of the invadopodia-like protrusions (white arrows in F, G).</p>", "links"=>[], "tags"=>["inhibition", "rescues", "invadopodia-like", "protrusions"], "article_id"=>252997, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g005", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Src_inhibition_rescues_invasion_but_not_formation_of_invadopodia_like_protrusions_in_mlt_/252997", "title"=>"Src inhibition rescues invasion but not formation of invadopodia-like protrusions in <i>mlt</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 00:49:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/583288"], "description"=>"<p>(A) In <i>mlt</i> heterozygotes the expression of mutant Myh11 protein does not generate sufficient smooth muscle tension to induce epithelial invasion or stratification (0). Menadione treatment induces ROS production in the epithelium (1). Epithelial ROS signaling leads to premature phosphorylation of Caldesmon in heterozygous smooth muscle cells (2). The resulting increase in smooth muscle tone (3) leads to an amplified ROS response in the epithelium (4), establishing a feed forward loop causing additional h-CaD phosphorylation and increased smooth muscle tension. Together these stimuli induce invasive remodeling of the epithelium (5). (B) Endogenous smooth muscle tone in <i>mlt</i> homozygous larvae (0) induces epithelial ROS (1) and h-CaD phosphorylation via epithelial signaling (2, 3). Ultimately, this culminates in epithelial invasion (4), as in menadione treated <i>mlt</i> heterozygotes.</p>", "links"=>[], "tags"=>["amplification", "signaling", "controls", "contraction"], "article_id"=>253778, "categories"=>["Chemistry", "Developmental Biology", "Biophysics", "Physiology", "Cell Biology", "Genetics"], "users"=>["Christoph Seiler", "Gangarao Davuluri", "Joshua Abrams", "Fitzroy J. Byfield", "Paul A. Janmey", "Michael Pack"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001386.g010", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_amplification_feedback_signaling_loop_controls_smooth_muscle_contraction_and_invasion_in_mlt_larvae_/253778", "title"=>"An amplification feedback signaling loop controls smooth muscle contraction and invasion in <i>mlt</i> larvae.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-04 01:02:58"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"7", "full-text"=>"10", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"6", "full-text"=>"3", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
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Relative Metric

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