Diaphragm defects occur in a CDH hernia model  independently of myogenesis and lung formation

Babiuk, Randal P.; Greer, John J.

doi:10.1152/ajplung.00257.2002

Cited by 102 publications

(89 citation statements)

References 29 publications

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“…ST8SIA2 is also an interesting candidate; this gene encodes a polysialyltransferase enzyme that is thought to play a role in the polysialylation of the neural cell adhesion molecule (21). This is of interest because polysialylated neural cell adhesion molecule is thought to play a role in the guidance of the phrenic nerve to the PPF and has been shown to be differentially expressed during myotube separation in the diaphragm, although the significance of this with regard to the development of CDH is unclear, because the pathogenesis of Bochdalek CDH does not appear to be related to diaphragm myogenesis and innervation (4,5,9). Below, we discuss the expression pattern of Igf1r, Rgma, and Coup-tfII in the PPF and the significance of this with regard to CDH.…”

Section: Discussionmentioning

confidence: 99%

Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia

Clugston

Zhang²,

Greer³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Clugston RD, Zhang W, Greer JJ. Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 294: L665-L675, 2008. First published February 8, 2008 doi:10.1152/ajplung.00027.2008.-Congenital diaphragmatic hernia (CDH) is a frequently occurring birth defect and a source of potentially fatal neonatal respiratory distress. Recently, through the application of detailed karyotyping methods, several CDH-critical regions within the human genome have been identified. These regions typically contain several genes. Here we focused on genes from 15q26, the best-characterized CDH-critical region, as well as FOG2 and GATA4, genes singled out from CDHcritical regions at 8q22-8q23 and 8p23.1, respectively. We tested the hypothesis that these putative CDH-related genes are expressed within the developing diaphragm at the time of the hypothesized initial defect. Our results show that 15q26 contains a cluster of genes that are expressed in the developing rodent diaphragm, consistent with an association between deletions in this region and CDH. We then examined the protein expression pattern of positively identified genes within the developing diaphragm. Two major themes emerged. First, those factors strongly associated with CDH are expressed only in the nonmuscular, mesenchymal component of the diaphragm, supporting the hypothesis that CDH has its origins in a mesenchymal defect. Second, these factors are all coexpressed in the same cells. This suggests that cases of CDH with unique genetic etiology may lead to a common defect in these cells and supports the hypothesis that these factors may be members of a common pathway. This study is the first to provide a detailed examination of how genes associated with CDH are expressed in the developing diaphragm and provides an important foundation for understanding how the deletion of specific genes may contribute to abnormal diaphragm formation.

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Section: Discussionmentioning

confidence: 99%

Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia

Clugston

Zhang²,

Greer³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…That data led to the hypothesis stating that the amuscular mesenchymal component of the PPF, likely derived from the somatopleure, is defective and does not provide a full foundation for the formation of diaphragmatic musculature. We tested the hypothesis using mice in which muscle precursors fail to migrate to peripheral muscle, including the diaphragm, due to homozygous mutation (Ϫ/Ϫ) of the c-met gene (20). While the diaphragmatic musculature fails to form in the null-mutants, the underlying connective tissue that comprises the amuscular substratum forms fully, thus, offering the opportunity to clearly visualize the formation of the amuscular component of the diaphragm in normal and nitrofen-exposed animals.…”

Section: Insights Into the Pathogenesis Of Cdh From Animal Modelsmentioning

confidence: 99%

“…Implicit in that hypothesis is the notion that diaphragm embryogenesis is regulated or influenced directly by the development of the adjacent lung tissue. Recently, FGF10 null-mutant mice that do not develop lung tissue have been used to address this issue (20). Specifically, it was tested whether or not lung tissue was necessary for 1) normal diaphragm formation and 2) diaphragm defects in animal model of CDH.…”

Section: Insights Into the Pathogenesis Of Cdh From Animal Modelsmentioning

confidence: 99%

Etiology of Congenital Diaphragmatic Hernia: The Retinoid Hypothesis

2003

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Congenital diaphragmatic hernia (CDH) is a major lifethreatening cause of respiratory failure in the newborn. Although significant efforts have been undertaken to unravel the pathophysiology of CDH, our current understanding of the etiology remains spare. Here we outline recent evidence suggesting that abnormalities linked with the retinoid signaling pathway early in gestation may contribute to the etiology of CDH. These studies include 1) the effect of altering the retinoid system in vitamin A deficient and transgenic animals; 2) disruption of the retinoid system in teratogen-induced CDH in rodents, 3) the effect of co-administration of retinoids in nitrofen-induced CDH on lung and diaphragm development, and 4) clinical evidence suggesting decreased markers of vitamin A status in human CDH. Given the substantial mortality and morbidity associated with this serious developmental anomaly, advancements in this area will be critical. We feel that there is now sufficient circumstantial and direct experimental evidence to warrant further testing of the retinoid-CDH etiology hypothesis, including examination of retinoidregulated target genes that could be candidates for involvement in CDH. Severe respiratory failure in the newborn remains a main cause of neonatal death (1). Among the causes of severe respiratory failure in the newborn, congenital diaphragmatic hernia (CDH) remains the most life threatening (2, 3). Despite improvements in survival, the mortality rate is still high in many centers, and morbidity remains significant, with chronic oxygen dependence, gastroesophageal reflux, poor growth and developmental delay, and prolonged postoperative hospitalization of affected neonates (4). A major factor limiting survival in CDH is the degree of lung hypoplasia. Although tremendous efforts have been undertaken to unravel the pathophysiology of CDH, our current understanding of the pathogenesis and etiology remains spare. In this perspective, we review evidence linking abnormalities of the retinoid system and the occurrence of CDH. From the outset, it should be emphasized that a direct linkage between the etiology of CDH and retinoids has not been established. However, we summarize data from a variety of studies that provide a firm foundation for establishing the hypothesis that abnormalities within the retinoid signaling pathway during the early gestation contribute to the etiology of CDH. CONGENITAL DIAPHRAGMATIC HERNIA: THE CLINICAL DILEMMACDH occurs in 1/2500 live births (5). This malformation was first described in 1848 by Bochdalek, and for many years was thought to be a simple hole in the diaphragm, potentially curable by surgical closure of the defect after birth. However, unlike other causes of respiratory failure in the newborn, infants with CDH do not respond to our modern therapeutic armamentarium, including exogenous surfactant, high frequency oscillatory ventilation and inhaled nitric oxide (6). When conventional therapy fails, extra-corporeal membrane oxygenation (ECMO), a highly invasive, labor-intens...

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“…The mature fetal diaphragm is made up of muscular regions composed of hypaxial-derived skeletal muscle, an amuscular region called the central tendon, and the crural diaphragm (7,9). Because diaphragmatic hernias are believed to occur through a mechanism that affects nonmuscle mesenchymal cells (10), it is necessary to investigate the molecular basis controlling diaphragmatic mesenchymal cell proliferation, patterning, and differentiation.…”

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confidence: 99%

Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia

Coles¹,

Ackerman

2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Human congenital diaphragmatic defects are almost as common as cystic fibrosis, cause neonatal mortality, and often result in multisystem morbidity throughout childhood. Research investigating mechanisms of development is needed to understand the pathogenesis of disease. In this report, we identified a model caused by a mutation in kinesin motor family gene kinesin family member 7 . We determined that this gene is required to regulate cell proliferation, patterning, and differentiation in the embryonic diaphragm. We ascertained several functions of retinoid signaling in diaphragm development and gained insight into how perturbations in this signaling network promote the pathogenesis of congenital diaphragmatic hernia.

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Diaphragm defects occur in a CDH hernia model independently of myogenesis and lung formation

Cited by 102 publications

References 29 publications

Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia

Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia

Etiology of Congenital Diaphragmatic Hernia: The Retinoid Hypothesis

Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia

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