Abstract
BackgroundInsulin-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.Methods/Principal FindingsPrenatal 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/SignificanceWe 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.
Highlights
Insulin-like Growth Factor 1 (IGF1) is a member of the insulin family involved in the control of tissue development and homeostasis by regulating multiple cell functions including proliferation, differentiation, survival, adhesion and migration
In Igf12/2 E18.5 embryos, the lung-to-body-weight ratio was highly reduced when compared to Igf1+/+ controls, with a significant reduction, 50% compared to their normal littermates (Fig. 1A), demonstrating that IGF1 functions as a general growth factor for the entire organism during the embryonic period [12,13], its role is even more crucial for proper prenatal lung growth
The smaller size and reduced proliferation rates found in E12.5 Igf12/2 explanted lungs suggests that the disproportional growth retardation of prenatal E18.5 Igf12/2 lungs could be a consequence of their diminished growth rates during early stages of organogenesis
Summary
Insulin-like Growth Factor 1 (IGF1) is a member of the insulin family involved in the control of tissue development and homeostasis by regulating multiple cell functions including proliferation, differentiation, survival, adhesion and migration. Several mutations in both IGF1 and IGF1R genes have been associated with intrauterine growth retardation [4,5]. One of these patients, with a deletion that included the IGF1R gene, was reported to have lung hypoplasia [6]. Parallel studies on genetically modified mice are contributing to better understanding the role of IGFs in pulmonary development and genetically support the fact that IGFs signaling contribute to the control of prenatal mouse lung growth and differentiation. Little is known about the cellular and molecular basis of IGF1 activity during lung development
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