Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Pediatric Surgery International
Published in: Pediatric Surgery International 1/2019

01-01-2019 | Original Article

Expression of dispatched RND transporter family member 1 is decreased in the diaphragmatic and pulmonary mesenchyme of nitrofen-induced congenital diaphragmatic hernia

Authors: Toshiaki Takahashi, Florian Friedmacher, Julia Zimmer, Prem Puri

Published in: Pediatric Surgery International | Issue 1/2019

Login to get access

Abstract

Purpose

Congenital diaphragmatic hernia (CDH) and associated pulmonary hypoplasia (PH) are thought to be caused by a malformation of the diaphragmatic and pulmonary mesenchyme. Dispatched RND transporter family member 1 (Disp-1) encodes a transmembrane protein that regulates the release of cholesterol and palmitoyl, which is critical for normal diaphragmatic and airway development. Disp-1 is strongly expressed in mesenchymal compartments of fetal diaphragms and lungs. Recently, Disp-1 mutations have been identified in patients with CDH. We hypothesized that diaphragmatic and pulmonary Disp-1 expression is decreased in the nitrofen-induced CDH model.

Methods

Time-mated rats received nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms and lungs were microdissected on selected endpoints D13, D15 and D18; and divided into control and nitrofen-exposed specimens (n = 12 per sample, time-point and experimental group). Diaphragmatic and pulmonary Disp-1 expression was evaluated by qRT-PCR. Immunofluorescence double staining for Disp-1 was combined with diaphragmatic and pulmonary mesenchymal markers Wt-1 and Sox-9 to localize protein expression in fetal diaphragms and lungs.

Results

Relative mRNA levels of Disp-1 were significantly decreased in pleuroperitoneal folds/primordial lungs on D13 (0.18 ± 0.08 vs. 0.46 ± 0.41; p < 0.05/1.06 ± 0.27 vs. 1.34 ± 0.79; p < 0.05), developing diaphragms/lungs on D15 (0.18 ± 0.06 vs. 0.44 ± 0.23; p < 0.05/0.73 ± 0.36 vs. 1.16 ± 0.27; p < 0.05) and fully muscularized diaphragms/differentiated lungs on D18 (0.22 ± 0.18 vs. 0.32 ± 0.23; p < 0.05/0.56 ± 0.16 vs. 0.77 ± 0.14; p < 0.05) of nitrofen-exposed fetuses compared to controls. Confocal laser scanning microscopy demonstrated markedly diminished Disp-1 immunofluorescence predominately in the diaphragmatic and pulmonary mesenchyme of nitrofen-exposed fetuses on D13, D15 and D18, associated with a clear reduction of proliferating mesenchymal cells.

Conclusions

Decreased Disp-1 expression during diaphragmatic development and lung branching morphogenesis may interrupt mesenchymal cell proliferation, thus leading to diaphragmatic defects and PH in the nitrofen-induced CDH model.
Literature
1.
Balayla J, Abenhaim HA (2014) Incidence, predictors and outcomes of congenital diaphragmatic hernia: a population-based study of 32 million births in the United States. J Matern Fetal Neonatal Med 27:1438–1444CrossRefPubMed
2.
McGivern MR, Best KE, Rankin J, Wellesley D, Greenlees R, Addor MC, Arriola L, de Walle H, Barisic I, Beres J, Bianchi F, Calzolari E, Doray B, Draper ES, Garne E, Gatt M, Haeusler M, Khoshnood B, Klungsoyr K, Latos-Bielenska A, O’Mahony M, Braz P, McDonnell B, Mullaney C, Nelen V, Queisser-Luft A, Randrianaivo H, Rissmann A, Rounding C, Sipek A, Thompson R, Tucker D, Wertelecki W, Martos C (2015) Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 100:F137–F144CrossRefPubMed
3.
Morini F, Capolupo I, van Weteringen W, Reiss I (2017) Ventilation modalities in infants with congenital diaphragmatic hernia. Semin Pediatr Surg 26:159–165CrossRefPubMed
4.
Harting MT, Lally KP (2014) The congenital diaphragmatic hernia study group registry update. Semin Fetal Neonatal Med 19:370–375CrossRefPubMed
5.
Greer JJ (2013) Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. Respir Physiol Neurobiol 189:232–240CrossRefPubMed
6.
Merrell AJ, Kardon G (2013) Development of the diaphragm—a skeletal muscle essential for mammalian respiration. FEBS J 280:4026–4035CrossRefPubMed
7.
Maki JM, Sormunen R, Lippo S, Kaarteenaho-Wiik R, Soininen R, Myllyharju J (2005) Lysyl oxidase is essential for normal development and function of the respiratory system and for the integrity of elastic and collagen fibers in various tissues. Am J Pathol 167:927–936CrossRefPubMedPubMedCentral
8.
Hornstra IK, Birge S, Starcher B, Bailey AJ, Mecham RP, Shapiro SD (2003) Lysyl oxidase is required for vascular and diaphragmatic development in mice. J Biol Chem 278:14387–14393CrossRefPubMed
9.
Clugston RD, Zhang W, Greer JJ (2010) Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia. Birth Defects Res A Clin Mol Teratol 88:15–24PubMed
10.
van Loenhout RB, Tibboel D, Post M, Keijzer R (2009) Congenital diaphragmatic hernia: comparison of animal models and relevance to the human situation. Neonatology 96:137–149CrossRefPubMed
11.
12.
Noble BR, Babiuk RP, Clugston RD, Underhill TM, Sun H, Kawaguchi R, Walfish PG, Blomhoff R, Gundersen TE, Greer JJ (2007) Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen. Am J Physiol Lung Cell Mol Physiol 293:L1079–L1087CrossRefPubMed
13.
Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT (2002) Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129:5753–5765CrossRefPubMed
14.
15.
Kantarci S, Ackerman KG, Russell MK, Longoni M, Sougnez C, Noonan KM, Hatchwell E, Zhang X, Pieretti-Vanmarcke R, Anyane-Yeboa K, Dickman P, Wilson J, Donahoe PK, Pober BR (2010) Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH. Am J Med Genet Part A 152:2493–2504CrossRef
16.
17.
Short K, Hodson M, Smyth I (2013) Spatial mapping and quantification of developmental branching morphogenesis. Development 140:471–478CrossRefPubMed
18.
Friedmacher F, Gosemann JH, Fujiwara N, Takahashi H, Hofmann A, Puri P (2013) Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia. Pediatr Surg Int 29:1193–1198CrossRefPubMed
19.
Babiuk RP, Zhang W, Clugston R, Allan DW, Greer JJ (2003) Embryological origins and development of the rat diaphragm. J Comp Neurol 455:477–487CrossRefPubMed
20.
Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA, Kardon G (2015) Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nat Genet 47:496–504CrossRefPubMedPubMedCentral
21.
Takahashi T, Friedmacher F, Takahashi H, Hofmann AD, Puri P (2015) Kif7 expression is decreased in the diaphragmatic and pulmonary mesenchyme of nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg 50:904–907CrossRefPubMed
22.
Takahashi T, Friedmacher F, Takahashi H, Daniel Hofmann A, Puri P (2014) Lysyl oxidase expression is decreased in the developing diaphragm and lungs of nitrofen-induced congenital diaphragmatic hernia. Eur J Pediatr Surg 25:15–19CrossRefPubMed
23.
Heussler HS, Suri M, Tibboel D, de Klein A, Lee B, Scott DA (2007) Genetic factors in congenital diaphragmatic hernia. Am J Hum Genet 80:825–845CrossRef
24.
Rottier R, Tibboel D (2005) Fetal lung and diaphragm development in congenital diaphragmatic hernia. Semin Perinatol 29:86–93CrossRefPubMed
25.
Unger S, Copland I, Tibboel D (2003) Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia. Am J Pathol 162(2):547–555CrossRefPubMedPubMedCentral
26.
Coles GL, Ackerman KG (2013) Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia. Proc Natl Acad Sci USA 110:E1898–E1905CrossRefPubMed
27.
Cheung HO, Zhang X, Ribeiro A (2009) The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal 2:ra29CrossRefPubMed
28.
Carmona R, Canete A, Cano E, Ariza L, Rojas A, Munoz-Chapuli R (2016) Conditional deletion of WT1 in the septum transversum mesenchyme causes congenital diaphragmatic hernia in mice. Elife 19:e16009CrossRef
29.
30.
Chang DR, Martinez Alanis D, Miller RK, Ji H, Akiyama H, McCrea PD, Chen J (2013) Lung epithelial branching program antagonizes alveolar differentiation. Proc Natl Acad Sci USA 110:18042–18051CrossRef
31.
Turcatel G, Rubin N, Menke DB, Martin G, Shi W, Warburton D (2013) Lung mesenchymal expression of Sox9 plays a critical role in tracheal development. BMC Biol 11:117CrossRefPubMedPubMedCentral
Metadata
Title
Expression of dispatched RND transporter family member 1 is decreased in the diaphragmatic and pulmonary mesenchyme of nitrofen-induced congenital diaphragmatic hernia
Authors
Toshiaki Takahashi
Florian Friedmacher
Julia Zimmer
Prem Puri
Publication date
01-01-2019
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Surgery International / Issue 1/2019
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI
https://doi.org/10.1007/s00383-018-4374-6

Other articles of this Issue 1/2019

Pediatric Surgery International 1/2019 Go to the issue

Original Article

Reoperation after Ladd’s procedure in the neonatal period

Original Article

Altered expression of inflammasomes in Hirschsprung’s disease

Original Article

Duodenal atresia and associated intestinal atresia: a cohort study and review of the literature

Original Article

The multi-disciplinary management of complex congenital and acquired tracheo-oesophageal fistulae

Original Article

Safety and usefulness of plastic closure in infants with gastroschisis: a systematic review and meta-analysis

Original Article

Melanoma in children, adolescents and young adults: anatomo-clinical features and prognostic study on 426 cases