The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development

Abstract

The embryonic expression of COUP-TFII, an orphan nuclear receptor, suggests that it may participate in mesenchymal-epithelial interactions required for organogenesis. Targeted deletion of the COUP-TFII gene results in embryonic lethality with defects in angiogenesis and heart development. COUP-TFII mutants are defective in remodeling the primitive capillary plexus into large and small microcapillaries. In the COUP-TFII mutant heart, the atria and sinus venosus fail to develop past the primitive tube stage. Reciprocal interactions between the endothelium and the mesenchyme in the vascular system and heart are essential for normal development of these systems. In fact, the expression of Angiopoietin-1, a proangiogenic soluble factor thought to mediate the mesenchymal-endothelial interactions during heart development and vascular remodeling, is down-regulated in COUP-TFII mutants. This down-regulation suggests that COUP-TFII may be required for bidirectional signaling between the endothelial and mesenchymal compartments essential for proper angiogenesis and heart development.

The expression pattern of nuclear receptors during cerebellar development

“…In general, COUP-TFI is more highly expressed in the neuronal tissue of the central and peripheral nervous systems, whereas COUP-TFII is expressed in the mesenchyme of developing organs (Pereira et al, 1995). Loss of function assays indicate that COUP-TFI is important for neurogenesis and neural crest cell differentiation during embryonic development Zhou et al, 2001;Yamaguchi et al, 2004), while COUP-TFII acts as a major regulator of angiogenesis, vein identity, and organ development (Pereira et al, 1999;Takamoto et al, 2005;You et al, 2005). In the cerebellum, the expressions patterns of these two receptors are not co-localized.…”

Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis

“…5), and by the left ventricle-specific expression of the closely related factor Hand1 (refs 5,6). Many chamber-specific transcription factors have subsequently been described [7][8][9] . The evidence of segmental regulation of cardiac transcription provides a mechanistic context for examining congenital heart defects in humans, which typically affect only a single chamber or region of the heart.…”

Angiopoietin 1 expression levels in the myocardium direct coronary vessel development

“…Our finding of a lack of coronary vessels appears to arise from problems with the proper formation and maintenance of the epicardium, similar to the ␣4 integrin (Yang et al, 1995), VCAM (Kwee et al, 1995), and WT1 (Moore et al, 1999) null mice. Ang1 mRNA is expressed at high levels in the heart region by E9.5 (Pereira et al, 1999) as is Tie2 mRNA (Dumont et al, 1992), suggesting a role for this signaling system in early heart development. The observation that Tie2 expression is found in the highly motile angioblast cells (Dumont et al, 1992) in addition to the developing epicardium suggests that these cells are programmed to respond to numerous environmental cues, including the local myocardial-produced Ang1.…”