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

Abstract

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.

Congenital Diaphragmatic Hernia in a Fetus with a De novo Terminal Deletion of Chromosome 15q26.1

“…They concluded that the 15q26 critical region contains a cluster of genes, such as MEF2A, NR2F2, and CHD2, that are expressed in rodent diaphragm development, thus supporting other reports that deletions in this region are associated with CDH [8].…”

“…Clugston et al [8] used rodent diaphragms to study the expression of CDH candidate genes from 15q26, as well as FOG2 and GATA4, two genes in other CDH critical regions at 8q22-q23 and 8p23.1, respectively [8]. They concluded that the 15q26 critical region contains a cluster of genes, such as MEF2A, NR2F2, and CHD2, that are expressed in rodent diaphragm development, thus supporting other reports that deletions in this region are associated with CDH [8].…”

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

“…1 I and J). To determine the cell type that contributes to the diaphragmatic tissue overgrowth, we examined the expression of myosin heavy chain (MyHC) and Wilms tumor-1 (Wt1) in sections of Kif7 dd/dd embryos; MyHC labels diaphragmatic skeletal muscle, and Wt1 is expressed in the early mesothelium and throughout the nonmuscle mesenchymal cells of the diaphragm (24,25). We determined that the skeletal muscle fiber distribution and orientation were normal at E13.5, whereas the nonmuscular Wt1 + cells accumulated throughout the mutant diaphragms ( Fig.…”

Dietary vitamin A intake below the recommended daily intake during pregnancy and the risk of congenital diaphragmatic hernia in the offspring

“…In animal models, a CDH-like phenotype has been linked to a deficient maternal intake of vitamin A (Anderson, 1941), teratogenic disturbances of retinoid homeostasis (Mey et al, 2003), genetic defects in retinoid signaling (Mendelsohn et al, 1994), and the expression of retinoid-related genes in the primordial diaphragm (Clugston et al, 2008). Noteworthy, administration of vitamin A reduced the incidence of CDH in animal models (Thébaud et al, 1999).…”