title: Knockout of insulin-like growth factor-1 receptor impairs distal lung morphogenesis.
abstract: BACKGROUND
  Insulin-like growth factors (IGF-I and -II) are pleiotropic regulators of somatic growth and development in vertebrate species. Endocrine and paracrine effects of both hormones are mediated by a common IGF type 1 receptor (IGF-1R). Lethal respiratory failure in neonatal IGF-1R knockout mice suggested a particular role for this receptor in pulmonary development, and we therefore investigated the consequences of IGF-1R inactivation in lung tissue.
  
  
  RESULTS
  We first generated compound heterozygous mutant mice harboring a hypomorphic (Igf1r(neo)) and a null (Igf1r(-)) allele. These IGF-1R(neo/-) mice express only 22% of normal IGF-1R levels and are viable. In adult IGF-1R(neo/-) mice, we assessed lung morphology and respiratory physiology and found normal histomorphometric characteristics and normal breathing response to hypercapnia. We then generated homozygous IGF-1R knockout mutants (IGF-1R(-/-)) and analyzed their lung development during late gestation using histomorphometric and immunohistochemical methods. IGF-1R(-/-) embryos displayed severe lung hypoplasia and markedly underdeveloped diaphragms, leading to lethal neonatal respiratory distress. Importantly, IGF-1R(-/-) lungs from late gestation embryos were four times smaller than control lungs and showed markedly thickened intersaccular mesenchyme, indicating strongly delayed lung maturation. Cell proliferation and apoptosis were significantly increased in IGF-1R(-/-) lung tissue as compared with IGF-1R(+/+) controls. Immunohistochemistry using pro-SP-C, NKX2-1, CD31 and vWF as markers revealed a delay in cell differentiation and arrest in the canalicular stage of prenatal respiratory organ development in IGF-1R(-/-) mutant mice.
  
  
  CONCLUSIONS
  We found that low levels of IGF-1R were sufficient to ensure normal lung development in mice. In contrast, complete absence of IGF-1R significantly delayed end-gestational lung maturation. Results indicate that IGF-1R plays essential roles in cell proliferation and timing of cell differentiation during fetal lung development.
authors.affiliation: INSERM UMRS 938, Hôpital Saint-Antoine, Paris, France.
authors.forename: Ralph
authors.initials: R
authors.lastname: Epaud
authors.forename: Flore
authors.initials: F
authors.lastname: Aubey
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Zayna
authors.initials: Z
authors.lastname: Chaker
authors.forename: Maud
authors.initials: M
authors.lastname: Clemessy
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dautin
authors.forename: Karmène
authors.initials: K
authors.lastname: Ahamed
authors.forename: Monique
authors.initials: M
authors.lastname: Bonora
authors.forename: Nadia
authors.initials: N
authors.lastname: Hoyeau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fléjou
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mailleux
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.forename: Alexandra
authors.initials: A
authors.lastname: Henrion-Caude
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D008168:Lung / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D012123:Pulmonary Ventilation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000172:deficiency* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D011374:Progesterone; D017526:Receptor, IGF Type 1