title: Thyroid follicle development requires Smad1/5- and endothelial cell-dependent basement membrane assembly.
abstract: Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. The developmental mechanisms of folliculogenesis, whereby follicles are formed by the reorganization of a non-structured mass of non-polarized epithelial cells, are largely unknown. Here we show that assembly of the epithelial basement membrane is crucial for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes. Thyroid-specific Smad1 and Smad5 double-knockout (Smad1/5(dKO)) mice displayed growth retardation, hypothyroidism and defective follicular architecture. In Smad1/5(dKO) embryonic thyroids, epithelial cells remained associated in large clusters and formed small follicles. Although similar follicular defects are found in Vegfa knockout (Vegfa(KO)) thyroids, Smad1/5(dKO) thyroids had normal endothelial cell density yet impaired endothelial differentiation. Interestingly, both Vegfa(KO) and Smad1/5(dKO) thyroids displayed impaired basement membrane assembly. Furthermore, conditioned medium (CM) from embryonic endothelial progenitor cells (eEPCs) rescued the folliculogenesis defects of both Smad1/5(dKO) and Vegfa(KO) thyroids. Laminin α1, β1 and γ1, abundantly released by eEPCs into CM, were crucial for folliculogenesis. Thus, epithelial Smad signaling and endothelial cell invasion promote folliculogenesis via assembly of the basement membrane.
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Mylah
authors.initials: M
authors.lastname: Villacorte
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Delmarcelle
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Manon
authors.initials: M
authors.lastname: Lernoux
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Mahé
authors.initials: M
authors.lastname: Bouquet
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Lemoine
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bolsée
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium Laboratory of Molecular Biology (Celgen), Stem Cell Biology and Embryology, KU Leuven, 2333 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susana Chuva
authors.initials: SC
authors.lastname: de Sousa Lopes
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Der Smissen
authors.affiliation: Department of Matrix Medicine, Faculty of Medicine, Oita University, 879-5593 Oita, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Guido
authors.initials: G
authors.lastname: Bommer
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Henriet
authors.affiliation: Department of Medicine, Pediatrics and Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
authors.affiliation: de Duve Institute and Université Catholique de Louvain, 1200 Brussels, Belgium christophe.pierreux@uclouvain.be.
authors.forename: Christophe E
authors.identifier: 0000-0002-9647-2816
authors.initials: CE
authors.lastname: Pierreux
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007037:Hypothyroidism / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D018345:Mice, Knockout; D038081:Organogenesis / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072637:Thyroid Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D024141:Collagen Type IV; D017077:Culture Media, Conditioned; D007797:Laminin; D051898:Smad1 Protein; D051902:Smad5 Protein; D042461:Vascular Endothelial Growth Factor A; C084098:laminin A
keywords: Epithelium; Extracellular matrix; Follicle; Mouse; Smad1; Smad5; Thyroid