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<title>Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity - PubMed</title>
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<meta name="description" content="The latent TGF-beta binding proteins (LTBP) -1, -3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-beta. The null mutation of LTBP-4S in mice causes defects in the differentiation of terminal air-sacs, fragmented elastin, and colon carcinomas. We invest …"><meta name="keywords" content="pmid:19016471, PMC2719250, doi:10.1002/jcp.21643, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov&#x27;t, Branka Dabovic, Yan Chen, Daniel B Rifkin, Animals, Benzamides / metabolism, Dioxoles / metabolism, Elastin / genetics, Elastin / metabolism*, Elastin / ultrastructure, Female, Latent TGF-beta Binding Proteins / genetics, Latent TGF-beta Binding Proteins / metabolism*, Lung / anatomy &amp; histology, Lung / embryology*, Lung / growth &amp; development*, Lung / metabolism, Male, Mice, Mice, Knockout, Phenotype, Pregnancy, Protein Isoforms / genetics, Protein Isoforms / metabolism*, Protein Serine-Threonine Kinases / antagonists &amp; inhibitors, Protein Serine-Threonine Kinases / metabolism, Pulmonary Alveoli / physiology, Pulmonary Alveoli / ultrastructure, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta / antagonists &amp; inhibitors, Receptors, Transforming Growth Factor beta / metabolism, Signal Transduction / physiology, Transforming Growth Factor beta / genetics, Transforming Growth Factor beta / metabolism*, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/19016471/"><meta property="og:description" content="The latent TGF-beta binding proteins (LTBP) -1, -3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-beta. The null mutation of LTBP-4S in mice causes defects in the differentiation of terminal air-sacs, fragmented elastin, and colon carcinomas. We invest …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/19016471/"><meta name="twitter:description" content="The latent TGF-beta binding proteins (LTBP) -1, -3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-beta. The null mutation of LTBP-4S in mice causes defects in the differentiation of terminal air-sacs, fragmented elastin, and colon carcinomas. We invest …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="EV5f7CeI3tllhAo2WBmSsoVRIDRAvivcVIPkKsH4D48Pb1uSzUZUWwrvgHzMoT3w">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="EV5f7CeI3tllhAo2WBmSsoVRIDRAvivcVIPkKsH4D48Pb1uSzUZUWwrvgHzMoT3w">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="EV5f7CeI3tllhAo2WBmSsoVRIDRAvivcVIPkKsH4D48Pb1uSzUZUWwrvgHzMoT3w">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="EV5f7CeI3tllhAo2WBmSsoVRIDRAvivcVIPkKsH4D48Pb1uSzUZUWwrvgHzMoT3w">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="EV5f7CeI3tllhAo2WBmSsoVRIDRAvivcVIPkKsH4D48Pb1uSzUZUWwrvgHzMoT3w">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="19016471">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1002/jcp.21643"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3058&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=19016471&amp;db=pubmed&amp;nlmid=0050222"
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Wiley
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/19016471/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=19016471&amp;db=pubmed&amp;nlmid=0050222"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="19016471"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/19016471/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/19016471/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="19016471" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F19016471%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="EV5f7CeI3tllhAo2WBmSsoVRIDRAvivcVIPkKsH4D48Pb1uSzUZUWwrvgHzMoT3w"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
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Abstract
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<p>
The latent TGF-beta binding proteins (LTBP) -1, -3, and -4 are extracellular proteins that assist in the secretion and localization of latent TGF-beta. The null mutation of LTBP-4S in mice causes defects in the differentiation of terminal air-sacs, fragmented elastin, and colon carcinomas. We investigated lung development from embryonic day 14.5 (E14.5) to day 7 after birth (P7) in order to determine when the defects in elastin organization initiate and to further examine the relation of TGF-beta signaling levels and air-sac septation in Ltbp4S-/- lungs. We found that defects in elastogenesis are visible as early as E14.5 and are maintained in the alveolar walls, in blood vessel media, and subjacent airway epithelium. The air-sac septation defect was associated with excessive TGF-beta signaling and was reversed by lowering TGF-beta2 levels. Thus, the phenotype is not directly reflective of a change in TGF-beta1, the only TGF-beta isoform known to complex with LTBP-4. Reversal of the air-sac septation defect was not associated with normalization of the elastogenesis indicating two separate functions of LTBP-4 as a regulator of elastic fiber assembly and TGF-beta levels in lungs.
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(c) 2008 Wiley-Liss, Inc.
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Defective terminal air-sac septation and… </p></div>
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<strong class="figure-label">
<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Defective terminal air-sac septation and elastic fiber formation in <i> Ltbp4S <sup> / </sup> </i> lungs. Upper… </p></div>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 1
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<div class="figure-caption-contents">Defective terminal air-sac septation and elastic fiber formation in <i>Ltbp4S<sup>/</sup></i> lungs. Upper panels show lung sections stained with H&amp;E, lower panels present orcinol-new fucsin staining of elastin. The arrows in upper panels point to terminal air-sacs; the arrows in the lower panels point to elastin. <b>A. P7</b> In WT lungs at P7 terminal air-sacs are divided into small units by the process of alveolarization, whereas in <i>Ltbp4S<sup>/</sup></i> lungs alveolarization is not uniform yielding regions with large terminal air-sacs. Elastin in the WT alveolar walls appears fibrillar, whereas in the <i>Ltbp4S<sup>/</sup></i> alveolar walls only globules of elastin were observed. <b>B. P0.5</b> At P0.5, the terminal air-sacs in <i>Ltbp4S<sup>/</sup></i> lungs are much larger than in WT lungs. The differences in elastin organization between WT and mutant lungs are similar to those illustrated in A. <b>C. E18.5</b> The difference in terminal air-sac septation and in elastin organization between WT and <i>Ltbp4S<sup>/</sup></i> lungs was already obvious at E18.5. <b>D and E. E16.5 and E14.5</b> No differences in WT and <i>Ltbp4S<sup>/</sup></i> lung histology were observed both at E16.5 and E14.5. However the differences in elastin organization were observed at E16.5 (<b>D</b>) and E14.5 (<b>E</b>). Bars: upper panels 200 µm, lower panels 20 µm.</div>
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Defective terminal air-sac septation and… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Defective terminal air-sac septation and elastic fiber formation in <i> Ltbp4S <sup> / </sup> </i> lungs. Upper… </p></div>
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<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 1
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<div class="figure-caption-contents">Defective terminal air-sac septation and elastic fiber formation in <i>Ltbp4S<sup>/</sup></i> lungs. Upper panels show lung sections stained with H&amp;E, lower panels present orcinol-new fucsin staining of elastin. The arrows in upper panels point to terminal air-sacs; the arrows in the lower panels point to elastin. <b>A. P7</b> In WT lungs at P7 terminal air-sacs are divided into small units by the process of alveolarization, whereas in <i>Ltbp4S<sup>/</sup></i> lungs alveolarization is not uniform yielding regions with large terminal air-sacs. Elastin in the WT alveolar walls appears fibrillar, whereas in the <i>Ltbp4S<sup>/</sup></i> alveolar walls only globules of elastin were observed. <b>B. P0.5</b> At P0.5, the terminal air-sacs in <i>Ltbp4S<sup>/</sup></i> lungs are much larger than in WT lungs. The differences in elastin organization between WT and mutant lungs are similar to those illustrated in A. <b>C. E18.5</b> The difference in terminal air-sac septation and in elastin organization between WT and <i>Ltbp4S<sup>/</sup></i> lungs was already obvious at E18.5. <b>D and E. E16.5 and E14.5</b> No differences in WT and <i>Ltbp4S<sup>/</sup></i> lung histology were observed both at E16.5 and E14.5. However the differences in elastin organization were observed at E16.5 (<b>D</b>) and E14.5 (<b>E</b>). Bars: upper panels 200 µm, lower panels 20 µm.</div>
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<p> Figure 1 </p>
</strong>
<div class="figure-caption-contents"><p> Defective terminal air-sac septation and… </p></div>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Defective terminal air-sac septation and elastic fiber formation in <i> Ltbp4S <sup> / </sup> </i> lungs. Upper… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1
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<div class="figure-caption-contents">Defective terminal air-sac septation and elastic fiber formation in <i>Ltbp4S<sup>/</sup></i> lungs. Upper panels show lung sections stained with H&amp;E, lower panels present orcinol-new fucsin staining of elastin. The arrows in upper panels point to terminal air-sacs; the arrows in the lower panels point to elastin. <b>A. P7</b> In WT lungs at P7 terminal air-sacs are divided into small units by the process of alveolarization, whereas in <i>Ltbp4S<sup>/</sup></i> lungs alveolarization is not uniform yielding regions with large terminal air-sacs. Elastin in the WT alveolar walls appears fibrillar, whereas in the <i>Ltbp4S<sup>/</sup></i> alveolar walls only globules of elastin were observed. <b>B. P0.5</b> At P0.5, the terminal air-sacs in <i>Ltbp4S<sup>/</sup></i> lungs are much larger than in WT lungs. The differences in elastin organization between WT and mutant lungs are similar to those illustrated in A. <b>C. E18.5</b> The difference in terminal air-sac septation and in elastin organization between WT and <i>Ltbp4S<sup>/</sup></i> lungs was already obvious at E18.5. <b>D and E. E16.5 and E14.5</b> No differences in WT and <i>Ltbp4S<sup>/</sup></i> lung histology were observed both at E16.5 and E14.5. However the differences in elastin organization were observed at E16.5 (<b>D</b>) and E14.5 (<b>E</b>). Bars: upper panels 200 µm, lower panels 20 µm.</div>
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<strong class="figure-label">
<p> Figure 2 </p>
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<div class="figure-caption-contents"><p> Electron micrography of P0.5 WT… </p></div>
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<strong class="figure-label">
<p> Figure 2 </p>
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<div class="figure-caption-contents"><p> Electron micrography of P0.5 WT and <i> Ltbp4S <sup> / </sup> </i> lungs. <b> A </b> Alveolar tips. <b> B… </b> </p></div>
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Figure 2
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<div class="figure-caption-contents">Electron micrography of P0.5 WT and <i>Ltbp4S<sup>/</sup></i> lungs. <b>A</b> Alveolar tips. <b>B</b> Airways. <b>C</b> Blood vessels. The lack of continuous lamellae in the mutant blood vessels is clear in C where there are essentially no ordered lamellae. E elastin, RBC red blood cell, SMC - smooth muscle cell, EP epithelial cell. Arrows point to elastic lamellae in the walls of blood vessels. Bars: A 0.5 m, B - 0.2 µm, C - 2 µm.</div>
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<p> Figure 3 </p>
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<div class="figure-caption-contents"><p> Ultrastructure of elastic fibers in… </p></div>
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<p> Figure 3 </p>
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<div class="figure-caption-contents"><p> Ultrastructure of elastic fibers in 4-week-old WT <i> and Ltbp4S <sup> / </sup> </i> mice. <b> A </b> -… </p></div>
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Figure 3
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<div class="figure-caption-contents">Ultrastructure of elastic fibers in 4-week-old WT <i>and Ltbp4S<sup>/</sup></i> mice. <b>A</b> - airways, <b>B</b>- dermis. In WT tissues the microfibrils are enmeshed in the elastin, whereas in <i>Ltbp4S<sup>/</sup></i> tissues large globules of elastin localize next to the microfibrils. COL- Collagen, EP epithelial cell, E- elastin, MF- microfibrils. Bars: A - 0.5 µm, B 0.2 µm.</div>
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<p> Figure 4 </p>
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<div class="figure-caption-contents"><p> Increased TGF-β signaling in <i> Ltbp4S… </i> </p></div>
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<p> Figure 4 </p>
</strong>
<div class="figure-caption-contents"><p> Increased TGF-β signaling in <i> Ltbp4S <sup> / </sup> </i> lungs. <b> A </b> Immunohistochemistry with P-Smad2 antibody revealed… </p></div>
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Figure 4
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<div class="figure-caption-contents">Increased TGF-β signaling in <i>Ltbp4S<sup>/</sup></i> lungs. <b>A</b> Immunohistochemistry with P-Smad2 antibody revealed a higher number of positive cell nuclei in <i>Ltbp4S<sup>/</sup></i> lungs. The arrows point to the P-Smad2 positive nuclei. <b>B</b> Quantitative Western Blot analysis of P-Smad2 in the lungs from 2 WT <i>and 2 Ltbp4S<sup>/</sup></i> P7 mice. The numbers at the bottom indicate the ratio of the intensity of P-Smad2 vs. Smad2/3 in the <i>Ltbp4S<sup>/</sup> samples normalized</i> to the P-Smad2 to Smad2/3 ratio in the WT samples. The ratio of the intensity of the P-Smad2 and the Smad2/3 bands was equivalent in both WT samples. The result shown is representative of four experiments using different animals. <b>C</b> Graphic representation of expression of <i>TTF</i> and <i>HNF-3h</i> in WT and mutant lungs. The expression of both genes was enhanced in <i>Ltbp4S<sup>/</sup></i> mice indicating increased TGF-β levels. Bar: 5 µm.</div>
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<p> Figure 5 </p>
</strong>
<div class="figure-caption-contents"><p> Rescued lung development in <i> Ltbp4S… </i> </p></div>
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<p> Figure 5 </p>
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<div class="figure-caption-contents"><p> Rescued lung development in <i> Ltbp4S <sup> / </sup> ;Tgfb2 <sup> / </sup> lungs. </i> <b> A </b> Histological analysis of… </p></div>
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Figure 5
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<div class="figure-caption-contents">Rescued lung development in <i>Ltbp4S<sup>/</sup>;Tgfb2<sup>/</sup> lungs.</i><b>A</b> Histological analysis of WT, <i>Ltbp4S<sup>/</sup>, Tgfb2<sup>/</sup></i> and <i>Ltbp4S<sup>/</sup>;Tgfb2<sup>/</sup></i> indicated improved terminal air-sac septation in <i>Ltbp4S<sup>/</sup>;Tgfb<sup>/</sup></i> compared to <i>Ltbp4S<sup>/</sup></i> lungs. Bars: 200 µm <b>B</b> Histomorphometric studies showed a complete rescue of lung development in <i>Ltbp4S<sup>/</sup>;Tgfb2<sup>/</sup></i> lungs, as measured by average terminal air-sac diameter. Four animals of each genotype were analyzed in this study. Bar: 200 µm.</div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Decreasing TGF-β2 levels in <i> Ltbp4S… </i> </p></div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Decreasing TGF-β2 levels in <i> Ltbp4S <sup> / </sup> </i> lungs does not rescue elastic fiber formation.… </p></div>
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Figure 6
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<div class="figure-caption-contents">Decreasing TGF-β2 levels in <i>Ltbp4S<sup>/</sup></i> lungs does not rescue elastic fiber formation. Under conditions in which terminal air-sac septation was normalized (Fig. 5A and B), elastogenesis was still defective as indicated by the absence of elastic lamellae. Elastin in sections from P0.5 lungs was stained with orcinol - new fuchsin. The arrows point to the elastic fibers in WT and <i>Tgfb2<sup>/</sup></i> lungs and to the globular elastin in <i>Ltbp4S<sup>/</sup></i> and <i>Ltbp4S<sup>/</sup></i>;<i>Tgfb2<sup>/</sup></i> lungs. Bar: 10 µm.</div>
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