L’Université de Cergy recrute un-e Enseignant-e Chercheur-se en Biologie Cellulaire et Biochimie pour la rentrée 2023, et pour une activité de recherche au sein du laboratoire ERRMECE, dans l’équipe Mec-Up qui étudie l’influence du microenvironnement
sénescent sur la dissémination tumorale. N’hésitez pas à candidater (CV et lettre de motivation) aupres de cedric.picot@cyu.fr. Pour plus d’infos : Offre de CDD Ens Chercheur-MecUp

Félicitations à l’équipe de Carine Le Goff (INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, Université Paris Cité) et ses collaborateurs pour leur dernière publication dans Human Molecular Genetics !

Laure Delhon, Zakaria Mougin, Jérémie Jonquet, Angélique Bibimbou, Johanne Dubail, Cynthia Bou-Chaaya, Nicolas Goudin, Wilfried Le Goff, Catherine Boileau, Valérie Cormier-Daire, Carine Le Goff, The critical role of the TB5 domain of fibrillin-1 in endochondral ossification, Human Molecular Genetics, Volume 31, Issue 22, 15 November 2022, Pages 3777–3788, https://doi.org/10.1093/hmg/ddac131

Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-β binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1^Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1^Y1698C/+ and Fbn1^{Y1698C/Y1698C} mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.

Bravo et merci à Charlie Colin Pierre et ses collaborateurs de l’équipe de Stéphane Brezillon (Université de Reims Champagne-Ardenne, Laboratoire MEDyC, CNRS UMR 7369) pour cette revue très complète en open access dans « Regenerative Medicine ».  Colin-Pierre C, El Baraka O, Danoux L, Bardey V, André V, Ramont L, Brézillon S. NPJ Regen Med. 2022 Dec 28;7(1):77. https://doi.org/10.1038/s41536-022-00267-y PMID: 36577752.

Heparan sulfate proteoglycans (HSPGs) are part of proteoglycan family. They are composed of heparan sulfate (HS)-type glycosaminoglycan (GAG) chains covalently linked to a core protein. By interacting with growth factors and/or receptors, they regulate numerous pathways including Wnt, hedgehog (Hh), bone morphogenic protein (BMP) and fibroblast growth factor (FGF) pathways. They act as inhibitor or activator of these pathways to modulate embryonic and adult stem cell fate during organ morphogenesis, regeneration and homeostasis. This review summarizes the knowledge on HSPG structure and classification and explores several signaling pathways regulated by HSPGs in stem cell fate. A specific focus on hair follicle stem cell fate and the possibility to target HSPGs in order to tackle hair loss are discussed in more dermatological and cosmeceutical perspectives.

Félicitations à l’équipe de Stéphane Brezillon et ses collaborateurs pour leur nouvelle publication dans « Am J Physiol Cell Physiol. » sur le rôle des SLRP et de leurs chaines de GAG dans la régulation de l’activité de MMP-14 !

Rivet R, Rao RM, Nizet P, Belloy N, Huber L, Dauchez M, Ramont L, Baud S, Brézillon S. Am J Physiol Cell Physiol. 2022 Dec 19. doi: 10.1152/ajpcell.00429.2022. Online ahead of print.PMID: 36534501

Small leucine-rich proteoglycans (SLRPs) are major regulators of extracellular matrix assembly and cell signaling. Lumican, a member of the SLRPs family, and its derived peptides possess anti-tumor activity by interacting directly with the catalytic domain of MMP-14 leading to the inhibition of its activity. The aim of this report was to characterize by in silico 3D modeling the structure and the dynamics of four SLRPs including their core protein and their specific polysaccharide chains to assess their capacity to bind to MMP-14 and to regulate its activity. Molecular docking experiments were performed to identify the specific amino acids of MMP-14 interacting with each of the four SLRPs. The inhibition of each SLRP (100nM) on MMP-14 activity and the constants of inhibition (Ki) were evaluated. The impact of the number of glycan chains, structures and dynamics of lumican on the interaction with MMP-14 was assessed by molecular dynamics simulations. Molecular docking analysis showed that all SLRPs bind to MMP-14 through their concave face, but in different regions of the catalytic domain of MMP-14. Each SLRPs inhibited significantly the MMP-14 activity. Finally, molecular dynamics showed the role of glycan chains in interaction with MMP-14 and shielding effect of SLRPs. Altogether, the results demonstrated that each SLRP exhibited inhibition of MMP-14 activity. However, the differential targeting of MMP-14 by the SLRPs was shown to be related not only to the core protein conformation but also to the glycan chain structures and dynamics.

Profs Dimitrios Zevgolis and Nikos Karamanos are putting together a Special Issue entitled ‘Extracellular matrix: The driving force of everything’ in Biomaterials and Biosystems (Elsevier). All papers will be peer-reviewed. Waived publication charges for 2022.

For more informations : Biomaterials and Biosystems | Journal | ScienceDirect.com by Elsevier

And contacts : dimitrios.zevgolis@ucd.ie; n.k.karamanos@upatras.gr; Emma.XU@elsevier.com

Zeinab Rekad est doctorante à l’Université de Nice Côte d’Azur. Elle réalise sa thèse dans le laboratoire d’Ellen Van Obberghen-Schilling à l’Institut de Biologie Valrose. Passionnée par la biologie des ARNs et la matrice extracellulaire, elle s’intéresse aux mécanismes de régulation des interactions entre les cellules et leur matrice extracellulaire et plus spécifiquement au rôle de la protéine liant les ARNs « SAM68 » dans l’adhésion des cellules endothéliales.

Dans cet article de revue, elle décrit avec ses co-auteurs, comment les différentes formes de « splicing » alternatif des gènes codant pour le matrisome impactent les propriétés structurales et fonctionnelles de la matrice extracellulaire et sont à l’origine de sa diversité, mais aussi en quoi des altérations de ces isoformes impactent plus largement l’homéostasie tissulaire et les processus oncogéniques.

https://doi.org/10.1016/j.matbio.2022.05.003

Highlights

•Environmental factors regulate spatial and temporal splicing of matrisome genes throughout life.

•Alternative splicing of matrisome genes drives structural and functional diversification of the ECM.

•Misregulation of ECM splicing isoforms impacts tissue homeostasis and oncogenic processes.

•We describe 4 easy ways to follow bioinformatics approaches to identify ECM gene splicing in cancer.