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

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          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.

          Methods/Principal Findings

          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/Significance

          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.

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          Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).

          Jeh-Ping Liu, Julie Baker, Archlbald Perkins … (1993)
          Newborn mice homozygous for a targeted disruption of insulin-like growth factor gene (Igf-1) exhibit a growth deficiency similar in severity to that previously observed in viable Igf-2 null mutants (60% of normal birthweight). Depending on genetic background, some of the Igf-1(-/-) dwarfs die shortly after birth, while others survive and reach adulthood. In contrast, null mutants for the Igf1r gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size). In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis. Igf-1(-/-)/Igf1r(-/-) double mutants did not differ in phenotype from Igf1r(-/-) single mutants, while in Igf-2(-)/Igf1r(-/-) and Igf-1(-/-)/Igf-2(-) double mutants, which are phenotypically identical, the dwarfism was further exacerbated (30% normal size). The roles of the IGFs in mouse embryonic development, as revealed from the phenotypic differences between these mutants, are discussed.
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            Role of insulin-like growth factors in embryonic and postnatal growth.

            Julie Baker, Jeh-Ping Liu, Elizabeth J. Robertson … (1993)
            A developmental analysis of growth kinetics in mouse embryos carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF1R), alone or in combination, defined the onset of mutational effects leading to growth deficiency and indicated that between embryonic days 11.0 and 12.5, IGF1R serves only the in vivo mitogenic signaling of IGF-II. From E13.5 onward, IGF1R interacts with both IGF-I and IGF-II, while IGF-II recognizes an additional unknown receptor (XR). In contrast with the embryo proper, placental growth is served exclusively by an IGF-II-XR interaction. Additional genetic data suggested that the type 2IGF/mannose 6-phosphate receptor is an unlikely candidate for XR. Postnatal growth curves indicated that surviving Igf-1(-/-) mutants, which are infertile and exhibit delayed bone development, continue to grow with a retarded rate after birth in comparison with wild-type littermates and become 30% of normal weight as adults.
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              Preparing for the first breath: genetic and cellular mechanisms in lung development.

              Edward Morrisey, Brigid L.M. Hogan (2010)
              The mammalian respiratory system--the trachea and the lungs--arises from the anterior foregut through a sequence of morphogenetic events involving reciprocal endodermal-mesodermal interactions. The lung itself consists of two highly branched, tree-like systems--the airways and the vasculature--that develop in a coordinated way from the primary bud stage to the generation of millions of alveolar gas exchange units. We are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes such as branching morphogenesis, vascular development, and the differentiation of multipotent progenitor populations. Nevertheless, many gaps remain in our knowledge, the filling of which is essential for understanding respiratory disorders, congenital defects in human neonates, and how the disruption of morphogenetic programs early in lung development can lead to deficiencies that persist throughout life. (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Rory Edward Morty: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 31 December 2013
                Volume: 8
                Issue: 12
                Electronic Location Identifier: e83028
                Affiliations
                [1 ]Centro de Investigación Biomédica de la Rioja, Fundación Rioja Salud, Logroño, Spain
                [2 ]Instituto de Biología Molecular y Celular del Cáncer - Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas – University of Salamanca, Salamanca, Spain
                University of Giessen Lung Center, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RSP NM-B IPL JDLR JGP. Performed the experiments: RSP NM-B IH-P IPL JDLR JGP. Analyzed the data: RSP NM-B IPL JDLR JGP. Contributed reagents/materials/analysis tools: RSP NM-B IH-P IPL JDLR JGP. Wrote the paper: RSP NM-B IH-P IPL JDLR JGP. These authors contributed equally to this work: RSP NM-B.

                [¤]

                Current address: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

                Article
                Publisher ID: PONE-D-13-26711
                DOI: 10.1371/journal.pone.0083028
                PMC ID: 3877002
                PubMed ID: 24391734
                SO-VID: d8ccdef2-599d-41dd-9dca-a3c2c677f889
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 27 June 2013
                Date accepted : 30 October 2013
                Page count
                Pages: 20
                Funding
                This work was partially supported by the Fundación Rioja Salud (Logroño) and Ministerio de Ciencia e Innovación (BFU200501437) (Spain). R.S.P. was a pre-doctoral fellow from Fundación Rioja Salud, N.M.-B. was a doctoral fellow from the Ministerio de Ciencia e Innovación and I.H.-P. was a JAE fellow from the Consejo Superior de Investigaciones Científicas (Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Endocrine System
                Subject: Endocrine Physiology
                Subject: Insulin-like Growth Factor
                Subject: Developmental Biology
                Subject: Cell Differentiation
                Subject: Molecular Development
                Subject: Genetics
                Subject: Animal Genetics
                Subject: Gene Expression
                Subject: Gene Networks
                Subject: Genetic Mutation
                Subject: Molecular Genetics
                Subject: Genomics
                Subject: Genome Analysis Tools
                Subject: Transcriptomes
                Subject: Histology
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Molecular Cell Biology
                Subject: Signal Transduction
                Subject: Signaling in Cellular Processes
                Subject: Transcriptional Signaling
                Subject: Cellular Types
                Subject: Extracellular Matrix
                Subject: Medicine
                Subject: Critical Care and Emergency Medicine
                Subject: Respiratory Failure
                Subject: Anatomy and Physiology
                Subject: Respiratory System
                Subject: Pediatrics
                Subject: Child Development
                Subject: Growth Retardation
                Subject: Pulmonology
                Subject: Pediatric Pulmonology

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                ScienceOpen disciplines: Uncategorized

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