title: Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation.
abstract: Type IV collagen is the main component of the basement membrane that gives strength to the blood-gas barrier (BGB). In mammals, the formation of a mature BGB occurs primarily after birth during alveologenesis and requires the formation of septa from the walls of the saccule. In contrast, in avians, the formation of the BGB occurs rapidly and prior to hatching. Mutation in basement membrane components results in an abnormal alveolar phenotype; however, the specific role of type IV collagen in regulating alveologenesis remains unknown.
  
  
  
  We have performed a microarray expression analysis in late chick lung development and found that COL4A1 and COL4A2 were among the most significantly upregulated genes during the formation of the avian BGB. Using mouse models, we discovered that mutations in murine Col4a1 and Col4a2 genes affected the balance between lung epithelial progenitors and differentiated cells. Mutations in Col4a1 derived from the vascular component were sufficient to cause defects in vascular development and the BGB. We also show that Col4a1 and Col4a2 mutants displayed disrupted myofibroblast proliferation, differentiation and migration. Lastly, we revealed that addition of type IV collagen protein induced myofibroblast proliferation and migration in monolayer culture and increased the formation of mesenchymal-epithelial septal-like structures in co-culture.
  
  
  
  Our study showed that type IV collagen and, therefore the basement membrane, play fundamental roles in coordinating alveolar morphogenesis. In addition to its role in the formation of epithelium and vasculature, type IV collagen appears to be key for alveolar myofibroblast development by inducing their proliferation, differentiation and migration throughout the developing septum.
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA. MLOSCERTALES@mgh.harvard.edu.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. MLOSCERTALES@mgh.harvard.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Loscertales
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Fotini
authors.initials: F
authors.lastname: Nicolaou
authors.affiliation: Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California, San Francisco, School of Medicine, San Francisco, CA, 94143, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Jeanne
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Longoni
authors.affiliation: Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California, San Francisco, School of Medicine, San Francisco, CA, 94143, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Faouzi I
authors.initials: FI
authors.lastname: Maalouf
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA.|Department of Human Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, 1094, Hungary.
authors.forename: Nandor
authors.initials: N
authors.lastname: Nagy
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, 02114, USA.|Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
mesh_terms: D000072283:A549 Cells; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D018920:Coculture Techniques; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D004847:Epithelial Cells / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009024:Morphogenesis; D009154:Mutation; D058628:Myofibroblasts / Q000166:cytology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C000619517:Col4a1 protein, mouse; C502624:Col4a2 protein, mouse; D024141:Collagen Type IV; D010446:Peptide Fragments
keywords: Alveolar development; Alveolar myofibroblast migration and differentiation; Basement membrane; Blood–gas barrier; Lung epithelium; Lung vasculature; Type IV collagen