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      Knockout of Insulin-Like Growth Factor-1 Receptor Impairs Distal Lung Morphogenesis

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          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.

          Methods and Findings

          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/Significance

          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.

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          Most cited references27

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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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            Transcriptional control of lung morphogenesis.

            Jeffrey A. Whitsett, Yutaka Maeda, Vrushank Davé (2006)
            The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), beta-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.
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              Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons.

              R. Widmer, F. Hefti, Francisco Valverde-Albacete … (1995)
              Homozygous Igf1-/- mice at 2 months of age had reduced brain weights, with reductions evenly affecting all major brain areas. The gross morphology of the CNS was normal, but the size of white matter structures in brain and spinal cord was strongly reduced, owing to decreased numbers of axons and oligodendrocytes. Myelinated axons were more strongly reduced in number than unmyelinated axons. The volume of the dentate gyrus granule cell layer was reduced in excess of the decrease in brain weight. Among populations of calcium-binding protein-containing neurons, there was a selective reduction in the number of striatal parvalbumin-containing cells. Numbers of mesencephalic dopaminergic neurons, striatal and basal forebrain cholinergic neurons, and spinal cord motoneurons were unaffected. Cerebellar morphology was unaltered. Our findings suggest cell type- and region-specific functions for IGF-I and emphasize prominent roles in axon growth and maturation in CNS myelination.
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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: 2012
                Publication date (Electronic): 6 November 2012
                Volume: 7
                Issue: 11
                Electronic Location Identifier: e48071
                Affiliations
                [1 ]INSERM UMRS 938, Hôpital Saint-Antoine, Paris, France
                [2 ]UPMC, Université Paris 6, Paris, France
                [3 ]INSERM U955, Faculté de Médecine, Université Paris-Est, Créteil, France
                [4 ]APHP, Hôpital Saint Antoine, Paris, France
                [5 ]INSERM UMR 700, Faculté Xavier Bichat, Paris, France
                [6 ]APHP, Hôpital Trousseau, Paris, France
                [7 ]INSERM UMRS 781, Hôpital Necker-Enfants Malades, Paris, France
                University of Giessen Lung Center, Germany
                Author notes

                These authors also contributed equally to this work.

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

                Conceived and designed the experiments: AC AHC JFF JX KA MB MC MH RE ZC. Performed the experiments: AD AM FA JX KA MB MC NH RE ZC. Analyzed the data: AD AM FA JX KA MB MC NH RE ZC. Wrote the paper: MH RE. Coordinated the study: AHC MH.

                Article
                Publisher ID: PONE-D-12-11538
                DOI: 10.1371/journal.pone.0048071
                PMC ID: 3491012
                PubMed ID: 23139760
                SO-VID: 0e4a31bb-d885-42e5-a8a2-a6df6e96e690
                Copyright statement: Copyright @ 2012
                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 : 20 April 2012
                Date accepted : 19 September 2012
                Page count
                Pages: 12
                Funding
                This work was supported by EU Network of Excellence LifeSpan (036894) and ANR (NT05-3 42491). Both funders supported salary and reagents. 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: Respiratory System
                Subject: Respiratory Physiology
                Subject: Developmental Biology
                Subject: Morphogenesis
                Subject: Growth Control
                Subject: Embryology
                Subject: Genetics
                Subject: Gene Function
                Subject: Histology
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Endocrinology
                Subject: Pediatric Endocrinology
                Subject: Pediatrics
                Subject: Growth Retardation
                Subject: Pulmonology
                Subject: Pediatric Pulmonology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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