FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor/ataxia syndrome
Identifieur interne : 000217 ( Pmc/Corpus ); précédent : 000216; suivant : 000218FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor/ataxia syndrome
Auteurs : Ronald Am Buijsen ; Chantal Sellier ; Lies-Anne Wfm Severijnen ; Mustapha Oulad-Abdelghani ; Rob Fm Verhagen ; Robert F. Berman ; Nicolas Charlet-Berguerand ; Rob Willemsen ; Renate K. HukemaSource :
- Acta Neuropathologica Communications [ 2051-5960 ] ; 2014.
Abstract
para
The online version of this article (doi:10.1186/s40478-014-0162-2) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s40478-014-0162-2
PubMed: 25471011
PubMed Central: 4254384
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor/ataxia syndrome</title><author><name sortKey="Buijsen, Ronald Am" sort="Buijsen, Ronald Am" uniqKey="Buijsen R" first="Ronald Am" last="Buijsen">Ronald Am Buijsen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Sellier, Chantal" sort="Sellier, Chantal" uniqKey="Sellier C" first="Chantal" last="Sellier">Chantal Sellier</name><affiliation><nlm:aff id="Aff2">Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</nlm:aff></affiliation></author><author><name sortKey="Severijnen, Lies Anne Wfm" sort="Severijnen, Lies Anne Wfm" uniqKey="Severijnen L" first="Lies-Anne Wfm" last="Severijnen">Lies-Anne Wfm Severijnen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Oulad Abdelghani, Mustapha" sort="Oulad Abdelghani, Mustapha" uniqKey="Oulad Abdelghani M" first="Mustapha" last="Oulad-Abdelghani">Mustapha Oulad-Abdelghani</name><affiliation><nlm:aff id="Aff2">Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</nlm:aff></affiliation></author><author><name sortKey="Verhagen, Rob Fm" sort="Verhagen, Rob Fm" uniqKey="Verhagen R" first="Rob Fm" last="Verhagen">Rob Fm Verhagen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Berman, Robert F" sort="Berman, Robert F" uniqKey="Berman R" first="Robert F" last="Berman">Robert F. Berman</name><affiliation><nlm:aff id="Aff3">Department of Neurological Surgery, UC Davis, Davis, CA 95618 USA</nlm:aff></affiliation></author><author><name sortKey="Charlet Berguerand, Nicolas" sort="Charlet Berguerand, Nicolas" uniqKey="Charlet Berguerand N" first="Nicolas" last="Charlet-Berguerand">Nicolas Charlet-Berguerand</name><affiliation><nlm:aff id="Aff2">Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</nlm:aff></affiliation></author><author><name sortKey="Willemsen, Rob" sort="Willemsen, Rob" uniqKey="Willemsen R" first="Rob" last="Willemsen">Rob Willemsen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hukema, Renate K" sort="Hukema, Renate K" uniqKey="Hukema R" first="Renate K" last="Hukema">Renate K. Hukema</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25471011</idno><idno type="pmc">4254384</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254384</idno><idno type="RBID">PMC:4254384</idno><idno type="doi">10.1186/s40478-014-0162-2</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000217</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000217</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor/ataxia syndrome</title><author><name sortKey="Buijsen, Ronald Am" sort="Buijsen, Ronald Am" uniqKey="Buijsen R" first="Ronald Am" last="Buijsen">Ronald Am Buijsen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Sellier, Chantal" sort="Sellier, Chantal" uniqKey="Sellier C" first="Chantal" last="Sellier">Chantal Sellier</name><affiliation><nlm:aff id="Aff2">Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</nlm:aff></affiliation></author><author><name sortKey="Severijnen, Lies Anne Wfm" sort="Severijnen, Lies Anne Wfm" uniqKey="Severijnen L" first="Lies-Anne Wfm" last="Severijnen">Lies-Anne Wfm Severijnen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Oulad Abdelghani, Mustapha" sort="Oulad Abdelghani, Mustapha" uniqKey="Oulad Abdelghani M" first="Mustapha" last="Oulad-Abdelghani">Mustapha Oulad-Abdelghani</name><affiliation><nlm:aff id="Aff2">Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</nlm:aff></affiliation></author><author><name sortKey="Verhagen, Rob Fm" sort="Verhagen, Rob Fm" uniqKey="Verhagen R" first="Rob Fm" last="Verhagen">Rob Fm Verhagen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Berman, Robert F" sort="Berman, Robert F" uniqKey="Berman R" first="Robert F" last="Berman">Robert F. Berman</name><affiliation><nlm:aff id="Aff3">Department of Neurological Surgery, UC Davis, Davis, CA 95618 USA</nlm:aff></affiliation></author><author><name sortKey="Charlet Berguerand, Nicolas" sort="Charlet Berguerand, Nicolas" uniqKey="Charlet Berguerand N" first="Nicolas" last="Charlet-Berguerand">Nicolas Charlet-Berguerand</name><affiliation><nlm:aff id="Aff2">Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</nlm:aff></affiliation></author><author><name sortKey="Willemsen, Rob" sort="Willemsen, Rob" uniqKey="Willemsen R" first="Rob" last="Willemsen">Rob Willemsen</name><affiliation><nlm:aff id="Aff1">Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hukema, Renate K" sort="Hukema, Renate K" uniqKey="Hukema R" first="Renate K" last="Hukema">Renate K. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Acta Neuropathol Commun</journal-id><journal-id journal-id-type="iso-abbrev">Acta Neuropathol Commun</journal-id><journal-title-group><journal-title>Acta Neuropathologica Communications</journal-title></journal-title-group><issn pub-type="epub">2051-5960</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25471011</article-id><article-id pub-id-type="pmc">4254384</article-id><article-id pub-id-type="publisher-id">162</article-id><article-id pub-id-type="doi">10.1186/s40478-014-0162-2</article-id><article-categories><subj-group subj-group-type="heading"><subject>Letter to the Editor</subject></subj-group></article-categories><title-group><article-title>FMRpolyG-positive inclusions in CNS and non-CNS organs of a fragile X premutation carrier with fragile X-associated tremor/ataxia syndrome</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Buijsen</surname><given-names>Ronald AM</given-names></name><address><email>r.buijsen@erasmusmc.nl</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Sellier</surname><given-names>Chantal</given-names></name><address><email>sellier@igbmc.fr</email></address><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Severijnen</surname><given-names>Lies-Anne WFM</given-names></name><address><email>e.severijnen@erasmusmc.nl</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Oulad-Abdelghani</surname><given-names>Mustapha</given-names></name><address><email>oulad@igbmc.fr</email></address><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Verhagen</surname><given-names>Rob FM</given-names></name><address><email>r.verhagen@erasmusmc.nl</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Berman</surname><given-names>Robert F</given-names></name><address><email>rfberman@ucdavis.edu</email></address><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Charlet-Berguerand</surname><given-names>Nicolas</given-names></name><address><email>ncharlet@igbmc.fr</email></address><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Willemsen</surname><given-names>Rob</given-names></name><address><email>r.willemsen@erasmusmc.nl</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Hukema</surname><given-names>Renate K</given-names></name><address><email>r.hukema@erasmusmc.nl</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><label></label>Department of Clinical Genetics, Erasmus, MC PO Box 2040, 3000CA The Netherlands</aff><aff id="Aff2"><label></label>Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France</aff><aff id="Aff3"><label></label>Department of Neurological Surgery, UC Davis, Davis, CA 95618 USA</aff></contrib-group><pub-date pub-type="epub"><day>26</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>26</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="collection"><year>2014</year></pub-date><volume>2</volume><elocation-id>162</elocation-id><history><date date-type="received"><day>8</day><month>10</month><year>2014</year></date><date date-type="accepted"><day>8</day><month>11</month><year>2014</year></date></history><permissions><copyright-statement>© Buijsen et al.; licensee BioMed Central Ltd. 2014</copyright-statement><license license-type="open-access"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><p>para</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s40478-014-0162-2) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>FXTAS</kwd><kwd>CGG repeat</kwd><kwd>FMRpolyG</kwd><kwd>RAN translation</kwd><kwd>Gain-of-function</kwd><kwd>Inclusions</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2014</meta-value></custom-meta></custom-meta-group></article-meta></front><body><p>Fragile X-associated Tremor/Ataxia syndrome (FXTAS), a late-onset monogenetic neurodegenerative disorder, is caused by a CGG-repeat expansion (55-200) in the 5′ UTR of the fragile-X mental retardation 1 gene (<italic>FMR1</italic>) on the X-chromosome [<xref ref-type="bibr" rid="CR1">1</xref>]. The prevalence of the <italic>FMR1</italic> premutation (PM) is about 1:855 in males and 1:291 in females [<xref ref-type="bibr" rid="CR2">2</xref>]. Approximately 45.5% of male and 16.5% of female PM carriers older than 50 years will develop signs of FXTAS [<xref ref-type="bibr" rid="CR3">3</xref>]. In addition to the core features of tremor and gait ataxia, unexplained medical co-morbidities have been reported, including thyroid disease, cardiac arrhythmias, hypertension, migraine, impotence, and neuropathy [<xref ref-type="bibr" rid="CR4">4</xref>]. PM carriers have increased levels of <italic>FMR1</italic> mRNA (2 to 8 fold in leucocytes) and normal to slightly reduced FMR1 protein (FMRP) levels [<xref ref-type="bibr" rid="CR5">5</xref>]. The current hypothesis is that FXTAS is caused by an RNA gain-of-function mechanism. Ubiquitin-positive intranuclear inclusions, are found in both brain and non-central nervous system (CNS) organs of patients with FXTAS [<xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR7">7</xref>]. So far, it is not clear whether these inclusions are protective or toxic. Recently, it has been hypothesized that repeat-associated non-AUG (RAN) translation plays a role in disease process and inclusion formation. Todd et al. [<xref ref-type="bibr" rid="CR8">8</xref>] demonstrated that through initiation at a near-ATG codon located in the 5′UTR of the <italic>FMR1</italic> gene a polyGlycine-containing protein, FMRpolyG, is expressed. This protein accumulates in ubiquitin-positive inclusions in <italic>Drosophila</italic>, cell culture, mouse disease models and brain from FXTAS patients. To investigate the link between FMRpolyG expression and the co-morbid medical problems associated with the PM we have developed two novel mouse monoclonal antibodies against polyGlycine; 8FM and 9FM (for epitopes and specificity see Additional file <xref rid="MOESM1" ref-type="media">1</xref>: Figure S1), and performed immunostaining in CNS as well as in non-CNS organs of FXTAS patient J.L. (case 6 in [<xref ref-type="bibr" rid="CR7">7</xref>]; other cases not available). To establish antibody specificity, we performed immunostaining with both antibodies on brain sections from FXTAS patient J.L., healthy non-demented controls (n = 3) and a patient with Parkinson disease, Alzheimer disease, or C9FTD. In hippocampus and cerebellum from FXTAS patient J.L. we identified FMRpolyG-positive inclusions with both 8FM (1:10) and 9FM (1:10) antibody (Figure <xref rid="Fig1" ref-type="fig">1</xref>a-b, Additional file <xref rid="MOESM2" ref-type="media">2</xref>: Figure S2a-b), as was described previously [<xref ref-type="bibr" rid="CR8">8</xref>]. None of the controls showed FMRpolyG-positive inclusions (data not shown). Next, we studied the immunolocalization of FMRpolyG protein in heart, kidney, adrenal gland and thyroid in patient J.L. with 8FM (1:10) and 9FM (1:10), compared to post mortem non-CNS somatic organ tissues from 3 healthy controls. We also examined tissues for FMRP (mouse T1A; 1:200) expression and ubiquitin-positive inclusions (DAKO, ZO458; 1:200). Consistent with our previous report [<xref ref-type="bibr" rid="CR7">7</xref>], ubiquitin-positive intranuclear inclusions were identified along with a normal distribution of FMRP (data not shown). Intranuclear FMRpolyG-positive inclusions could be detected in all organs examined (Figure <xref rid="Fig1" ref-type="fig">1</xref>c-h, Additional file <xref rid="MOESM2" ref-type="media">2</xref>: Figure S2c-h). No control tissues showed any FMRpolyG-positive inclusions (data not shown). Colocalization of ubiquitin- and FMRpolyG-positive inclusions was visualized and quantified by immunofluorescent double staining using antibodies against ubiquitin and FMRpolyG (8FM) (Figure <xref rid="Fig2" ref-type="fig">2</xref>a-f). For hippocampus, cerebellum and the non-CNS organs most inclusions are positive for both FMRpolyG and ubiquitin, although some rare inclusions positive for only one of the proteins could also be detected (Figure <xref rid="Fig2" ref-type="fig">2</xref>g, n = 100 inclusions). In conclusion, using two novel antibodies the present report not only confirms the existence of FMRpolyG-positive aggregates in CNS tissue from a FXTAS individual but also demonstrates for the first time the presence of FMRpolyG-positive intranuclear inclusions in post mortem non-CNS material of a PM carrier with FXTAS. Furthermore, colocalization of FMRpolyG and ubiquitin is found in the vast majority of inclusions. The presence of FMRpolyG-positive intranuclear inclusions in heart, kidney, adrenal gland and thyroid is consistent with the unexplained medical co-morbidities reported in some patients with FXTAS, including thyroid disease, cardiac arrhythmias, hypertension, migraine, impotence, and neuropathy. We hypothesize that the underlying pathological mechanisms of the medical co-morbidities in systemic tissues share common features (protein toxic gain-of-function) with CNS pathology of patients with FXTAS. Our report suggests that in addition to elevated levels of <italic>FMR1</italic> mRNA containing an expanded CGG repeat, and ubiquitin-positive inclusions, FMRpolyG expression might also play a role in a toxic gain-of-function mechanism in medical co-morbidities in FXTAS (RNA versus FMRpolyG toxic gain-of-function). Interestingly, a very recent report suggests that RAN translation products in C9FTD/ALS, toxic dipeptide repeat proteins (poly-(glycine-arginine) and poly-(proline-arginine)), are toxic in <italic>Drosophila</italic> [<xref ref-type="bibr" rid="CR9">9</xref>]. Further research is needed to understand how FMRpolyG may elicit toxicity in both CNS and non-CNS organs and its precise role in co-morbidities in PM carriers. Importantly, if FMRpolyG production is important for cellular toxicity this will open new avenues for therapeutic intervention studies for FXTAS by developing drugs that block this aberrant translation.<fig id="Fig1"><label>Figure 1</label><caption><p><bold>9FM FMRpolyG-positive intranuclear inclusions in hippocampus, cerebellum and non-CNS tissues of a FXTAS patient.</bold> FMRpolyG-positive (9FM) intranuclear inclusions in <bold>a</bold> hippocampus<bold>, b</bold> cerebellum, <bold>c</bold> glomeruli and <bold>d</bold> distal tubule of the kidney, <bold>e</bold> zona glomerulosa and <bold>f</bold> zona reticularis of adrenal gland, <bold>g</bold> cardiomyocytes and <bold>h</bold> thyroid. All sections were immunostained with 9FM antibody and counterstained with hematoxylin. Scale bars represent 50 μm.</p></caption><graphic xlink:href="40478_2014_162_Fig1_HTML" id="MO1"></graphic></fig><fig id="Fig2"><label>Figure 2</label><caption><p><bold>Colocalization of FMRpolyG (8FM) and ubiquitin in intranuclear inclusions in hippocampus, cerebellum and of non-CNS tissues of a FXTAS patient.</bold> Staining for ubiquitin (green), FMRpolyG (8FM; red) and DAPI (blue). Colocalization of ubiquitin and FMRpolyG (yellow) is seen in <bold>a</bold> hippocampus<bold>, b</bold> cerebellum, <bold>c</bold> kidney, <bold>d</bold> adrenal gland, <bold>e</bold> cardiomyocytes, and <bold>f</bold> thyroid; <bold>g</bold> quantification of inclusions containing ubiquitin and/or FMRpolyG (n = 100). Scale bars represent 10 μm.</p></caption><graphic xlink:href="40478_2014_162_Fig2_HTML" id="MO2"></graphic></fig></p></body><back><app-group><app id="App1"><sec id="Sec1"><title>Additional files</title><p><media position="anchor" xlink:href="40478_2014_162_MOESM1_ESM.pdf" id="MOESM1"><label>Additional file 1: Figure S1.</label><caption><p>Epitopes and specificity FMRpolyG antibodies 8FM and 9FM. a Sequence of the 5′UTR of human <italic>FMR1</italic> gene and the FMRpolyG peptide sequence resulting from RAN translation. Epitopes of 8FM and 9FM antibodies are boxed. b Monoclonal 8FM and 9FM antibodies were validated on COS7 cells transfected with pEGFP (Clonetech) plasmid containing the 5′UTR of <italic>FMR1</italic> with 5O CGG repeats, thus expressing the polyGlycine protein fused to GFP. On Western Blot a specific product could be detected for both antibodies and no product was detectable in COS7 cells transfected with a control GFP plasmid. c As an additional control experiment we performed immunostainings for 8FM antibody and could demonstrate specific intranuclear inclusions in COS7 cells transfected with a construct expressing the FMRpolyG fused to GFP, while cells tranfected with only GFP did not show any inclusion formation. Identical results were obtained with 9FM antibody (data not shown).</p></caption></media><media position="anchor" xlink:href="40478_2014_162_MOESM2_ESM.pdf" id="MOESM2"><label>Additional file 2: Figure S2.</label><caption><p>8FM FMRpolyG-positive intranuclear inclusions in hippocampus, cerebellum and non-CNS tissues of a FXTAS patient. FMRpolyG-positive (8FM) intranuclear inclusions in a hippocampus, b cerebellum, c glomeruli and d distal tubule of the kidney, e zona glomerulosa and f zona reticularis of adrenal gland, g cardiomyocytes and h thyroid. All sections were immunostained with 8FM antibody and counterstained with hematoxylin. Scale bars represent 50 μm.</p></caption></media></p></sec></app></app-group><glossary><title>Abbreviations</title><def-list><def-list><def-item><term>ALS</term><def><p>Amyotrophic lateral sclerosis</p></def></def-item><def-item><term>C9FTD</term><def><p>Chromosome 9 open reading frame 72 frontotemporal dementia</p></def></def-item><def-item><term>CNS</term><def><p>Central nervous system</p></def></def-item><def-item><term><italic>FMR1</italic></term><def><p>Fragile-X mental retardation 1</p></def></def-item><def-item><term>FMRP</term><def><p>Fragile-X mental retardation 1 protein</p></def></def-item><def-item><term>FXTAS</term><def><p>Fragile X-associated Tremor/Ataxia syndrome</p></def></def-item><def-item><term>PM</term><def><p>Fragile-X mental retardation 1 premutation</p></def></def-item><def-item><term>RAN</term><def><p>Repeat-associated non-AUG</p></def></def-item></def-list></def-list></glossary><fn-group><fn><p>Rob Willemsen and Renate K Hukema contributed equally</p></fn><fn><p><bold>Competing interests</bold></p><p>The authors declare that they have no competing interests.</p></fn><fn><p><bold>Authors’ contributions</bold></p><p>RAMB performed immunostainings and imaging, interpreted results, and drafted the manuscript. CS developed and validated antibodies. LAS performed immunostainings and imaging, and interpreted results. MOA developed and validated antibodies. RFMV performed immunostainings and imaging, and interpreted results. RFB interpreted results, drafted the manuscript and, obtained funding. NCB developed and validated antibodies, interpreted results, drafted the manuscript, and obtained funding. RW interpreted the results, drafted the manuscript, supervised the study, and obtained funding. RKH interpreted the results, drafted the manuscript, supervised the study, and obtained funding. RW and RKH contributed equally to this work. All authors read and approved the final manuscript.</p></fn></fn-group><ack><title>Acknowledgements</title><p>The authors wish to acknowledge the contribution of Tom de Vries Lentsch and Nathan Wubben. 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