title: Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.
abstract: BACKGROUND
  Insulin-like Growth Factor 1 (IGF1) is a multifunctional regulator of somatic growth and development throughout evolution. IGF1 signaling through IGF type 1 receptor (IGF1R) controls cell proliferation, survival and differentiation in multiple cell types. IGF1 deficiency in mice disrupts lung morphogenesis, causing altered prenatal pulmonary alveologenesis. Nevertheless, little is known about the cellular and molecular basis of IGF1 activity during lung development.
  
  
  RESULTS
  Prenatal Igf1(-/-) mutant mice with a C57Bl/6J genetic background displayed severe disproportional lung hypoplasia, leading to lethal neonatal respiratory distress. Immuno-histological analysis of their lungs showed a thickened mesenchyme, alterations in extracellular matrix deposition, thinner smooth muscles and dilated blood vessels, which indicated immature and delayed distal pulmonary organogenesis. Transcriptomic analysis of Igf1(-/-) E18.5 lungs using RNA microarrays identified deregulated genes related to vascularization, morphogenesis and cellular growth, and to MAP-kinase, Wnt and cell-adhesion pathways. Up-regulation of immunity-related genes was verified by an increase in inflammatory markers. Increased expression of Nfib and reduced expression of Klf2, Egr1 and Ctgf regulatory proteins as well as activation of ERK2 MAP-kinase were corroborated by Western blot. Among IGF-system genes only IGFBP2 revealed a reduction in mRNA expression in mutant lungs. Immuno-staining patterns for IGF1R and IGF2, similar in both genotypes, correlated to alterations found in specific cell compartments of Igf1(-/-) lungs. IGF1 addition to Igf1(-/-) embryonic lungs cultured ex vivo increased airway septa remodeling and distal epithelium maturation, processes accompanied by up-regulation of Nfib and Klf2 transcription factors and Cyr61 matricellular protein.
  
  
  CONCLUSIONS
  We demonstrated the functional tissue specific implication of IGF1 on fetal lung development in mice. Results revealed novel target genes and gene networks mediators of IGF1 action on pulmonary cellular proliferation, differentiation, adhesion and immunity, and on vascular and distal epithelium maturation during prenatal lung development.
authors.affiliation: Centro de Investigación Biomédica de la Rioja, Fundación Rioja Salud, Logroño, Spain.
authors.forename: Rosete Sofía
authors.initials: RS
authors.lastname: Pais
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer - Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas - University of Salamanca, Salamanca, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Moreno-Barriuso
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer - Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas - University of Salamanca, Salamanca, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández-Porras
authors.affiliation: Centro de Investigación Biomédica de la Rioja, Fundación Rioja Salud, Logroño, Spain.
authors.forename: Icíar Paula
authors.initials: IP
authors.lastname: López
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer - Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas - University of Salamanca, Salamanca, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: De Las Rivas
authors.affiliation: Centro de Investigación Biomédica de la Rioja, Fundación Rioja Salud, Logroño, Spain.
authors.forename: José García
authors.initials: JG
authors.lastname: Pichel
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics; D055515:Cysteine-Rich Protein 61 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008168:Lung / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000235:genetics; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C491850:CCN1 protein, mouse; C526318:CCN2 protein, mouse; D055515:Cysteine-Rich Protein 61; D018836:Inflammation Mediators; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051839:NFI Transcription Factors; C484683:Nfib protein, mouse; C519530:insulin-like growth factor-1, mouse; D055513:Connective Tissue Growth Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1