Musculocontractural Ehlers-Danlos syndrome and neurocristopathies : Dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin
Gouignard, Nadège LU ; Maccarana, Marco LU ; Strate, Ina LU ; von Stedingk, Kristoffer LU ; Malmström, Anders LU
and Pera, Edgar
LU
(2016)
In Disease Models and Mechanisms
9(6).
p.607-620
- Abstract
Of all live births with congenital anomalies, approximately one-third exhibit deformities ofthe head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused bydysfunction ofdermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE). Studies in mice have extended our understanding of DS-epi1 inconnective tissue maintenance; however, its role in fetal development is not understood. We demonstrate... (More)
Of all live births with congenital anomalies, approximately one-third exhibit deformities ofthe head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused bydysfunction ofdermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE). Studies in mice have extended our understanding of DS-epi1 inconnective tissue maintenance; however, its role in fetal development is not understood. We demonstrate that DS-epi1isimportant for the generationofisolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos. The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures. Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo. Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin. Thus, our work indicates a functional link between DS and NC cell migration. We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS, which might facilitate the diagnosis and development of therapies for this distressing condition. Moreover, the presented correlations between human DS-epi1 expression and gene sets of mesenchymal character, invasion and metastasis in neuroblastoma and malignant melanoma suggest an association between DS and NC-derived cancers.
(Less)
- author
- Gouignard, Nadège
LU
; Maccarana, Marco
LU
; Strate, Ina
LU
; von Stedingk, Kristoffer
LU
; Malmström, Anders
LU
and Pera, Edgar
LU
- organization
- publishing date
- 2016-06-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cancer, Cell migration, Dermatan sulfate, Musculocontractural Ehlers-Danlos syndrome, Neural crest, Xenopus
- in
- Disease Models and Mechanisms
- volume
- 9
- issue
- 6
- pages
- 14 pages
- publisher
- The Company of Biologists Ltd
- external identifiers
-
- scopus:84971441110
- pmid:27101845
- wos:000377088600003
- ISSN
- 1754-8403
- DOI
- 10.1242/dmm.024661
- language
- English
- LU publication?
- yes
- id
- f9012827-443d-4c84-96cb-06a4927e368e
- date added to LUP
- 2016-06-16 13:39:12
- date last changed
- 2024-02-18 22:57:29
@article{f9012827-443d-4c84-96cb-06a4927e368e,
abstract = {{<p>Of all live births with congenital anomalies, approximately one-third exhibit deformities ofthe head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused bydysfunction ofdermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE). Studies in mice have extended our understanding of DS-epi1 inconnective tissue maintenance; however, its role in fetal development is not understood. We demonstrate that DS-epi1isimportant for the generationofisolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos. The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures. Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo. Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin. Thus, our work indicates a functional link between DS and NC cell migration. We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS, which might facilitate the diagnosis and development of therapies for this distressing condition. Moreover, the presented correlations between human DS-epi1 expression and gene sets of mesenchymal character, invasion and metastasis in neuroblastoma and malignant melanoma suggest an association between DS and NC-derived cancers.</p>}},
author = {{Gouignard, Nadège and Maccarana, Marco and Strate, Ina and von Stedingk, Kristoffer and Malmström, Anders and Pera, Edgar}},
issn = {{1754-8403}},
keywords = {{Cancer; Cell migration; Dermatan sulfate; Musculocontractural Ehlers-Danlos syndrome; Neural crest; Xenopus}},
language = {{eng}},
month = {{06}},
number = {{6}},
pages = {{607--620}},
publisher = {{The Company of Biologists Ltd}},
series = {{Disease Models and Mechanisms}},
title = {{Musculocontractural Ehlers-Danlos syndrome and neurocristopathies : Dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin}},
url = {{http://dx.doi.org/10.1242/dmm.024661}},
doi = {{10.1242/dmm.024661}},
volume = {{9}},
year = {{2016}},
}