The role of JAK-STAT3 signaling pathway during fetal lung development

Nogueira‐Silva, Cristina; Nunes, Susana; Moura, Rute S.; Correia‐Pinto, Jorge

doi:10.1016/j.earlhumdev.2008.09.205

Cited by 1 publication

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“…7A–B ). Although downstream molecular pathways for IGF1/IGF1R signaling include the canonical Akt mediator, and activation of STAT3 transcription factor, both described to be involved in lung cells and lung development [69] , [70] , we did not find differences in their expression or activation levels ( Fig. 7A–B ).…”

Section: Resultsmentioning

confidence: 52%

“…Akt, STAT3 and MAP kinases, known as canonical IGF signaling mediators, were previously implicated in controlling cell proliferation, growth, survival and differentiation during lung development [60] , [69] – [73] . Furthermore, prenatal mouse cochleae of Igf1 −/− embryos showed decreased activation of prosurvival Akt and proliferation-associated ERK1/2 kinases, and increased levels of the stress kinase p38 [80] .…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome Analysis in Prenatal IGF1-Deficient Mice Identifies Molecular Pathways and Target Genes Involved in Distal Lung Differentiation

et al. 2013

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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.

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Section: Resultsmentioning

confidence: 52%