Mouse lackingCOUP-TFIIas an animal model of Bochdalek-type congenital diaphragmatic hernia

Abstract

Congenital diaphragmatic hernia (CDH), a life-threatening anomaly, is a major cause of pediatric mortality. Although the disease was described >350 years ago, the etiology of CDH is poorly understood. Here, we show that tissue-specific null mutants of COUP-TFII exhibit Bochdalek-type CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the posthepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Thus, both the stomach and liver enter the thoracic cavity, leading to lung hypoplasia and neonatal death. Recently a minimally deleted region for CDH has been identified on chromosome 15q26.1-26.2 by CGH array and FISH analysis. COUP-TFII is one of the four known genes residing within this critical region. Our finding suggests that COUP-TFII is a likely contributor to the formation of CDH in individuals with 15q deletions, and it may also be a potential contributor to some other Bochdalek-type of CDH.nuclear orphan receptor ͉ NR2F2

COUP-TFII controls amygdala patterning by regulating neuropilin expression

“…COUP-TFII (Nr2f2 -Mouse Genome Informatics), an orphan nuclear receptor, is essential for the morphogenesis of multiple organs (Takamoto et al, 2005a;Takamoto et al, 2005b;You et al, 2005a;You et al, 2005b;Kurihara et al, 2007;Petit et al, 2007;Li et al, 2009;Kim et al, 2009;Tang et al, 2010;Lin et al, 2010). In this study, we found that COUP-TFII was strongly expressed in the CGE, and we generated a conditional mutant that eliminated COUP-TFII function in the ventral telencephalon with RxCre.…”

PBX transcription factors drive pulmonary vascular adaptation to birth

“…These findings raise the possibility that there may be diaphragm-independent causes of lung abnormalities in CDH. Indeed, lung growth and patterning defects have been observed in animal models of CDH prior to normal diaphragm closure (14)(15)(16)(17)(18)(19). However, there has been no clear in vivo demonstration as yet that PH can arise independently of the diaphragmatic defect and herniation seen in CDH.…”

COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis

“…In the mouse, COUP-TFI and COUP-TFII (Nr2f1 and Nr2f2) are essential for early neural development and organogenesis (Qiu et al, 1997;Zhou et al, 1999;Pereira et al, 1999;You et al, 2005a;You et al, 2005b;Li et al, 2009;Kurihara et al, 2007;Petit et al, 2007;Takamoto et al, 2005a;Takamoto et al, 2005b). However, the physiological function of COUP-TFs in the mammalian eye has not been described.…”