Abstract-We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial (␣MHC-Creϩ), endocardial (Tie2-Creϩ), and neural crest (Wnt1-Creϩ) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation in the kidney, liver, and pancreas and is associated often with cardiovascular abnormalities such as hypertension, mitral valve prolapse, and intracranial aneurysms. It is caused by mutations in PKD1 or PKD2, encoding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel. Pkd2؊͞؊ mice have cysts in the kidney and pancreas and defects in cardiac septation, whereas Pkd1 del34 ؊͞؊ and Pkd1 L ؊͞؊ mice have cysts but no cardiac abnormalities, although vascular fragility was reported in the latter. Here we describe mice carrying a targeted mutation in Pkd1 (Pkd1 del17-21␤geo ), which defines its expression pattern by using a lacZ reporter gene and may identify novel functions for polycystin-1. Although Pkd1 del17-21␤geo ؉͞؊ adult mice develop renal and hepatic cysts, Pkd1 del17-21␤geo ؊͞؊ embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ventricle, disorganized myocardium, and abnormal atrio-ventricular septation. Skeletal development is also severely compromised. These abnormalities correlate with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 is expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincides with the onset of cyst formation in Pkd1 del34 ؊͞؊, Pkd1 L ؊͞؊, and Pkd2؊͞؊ mice, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function.

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We provide, for the first time, objective evidence of the mechanisms of closure of an AP foramen that exists distally between the lumens of the developing intrapericardial arterial trunks. Our findings provide insights into the formation of AP windows and the variants of common arterial trunk.

The dynamic properties of foldamers, synthetic molecules that mimic folded biomolecules, have mainly been explored in free solution. We report on the design, synthesis, and conformational behavior of photoresponsive foldamers bound in a phospholipid bilayer akin to a biological membrane phase. These molecules contain a chromophore, which can be switched between two configurations by different wavelengths of light, attached to a helical synthetic peptide that both promotes membrane insertion and communicates conformational change along its length. Light-induced structural changes in the chromophore are translated into global conformational changes, which are detected by monitoring the solid-state (19)F nuclear magnetic resonance signals of a remote fluorine-containing residue located 1 to 2 nanometers away. The behavior of the foldamers in the membrane phase is similar to that of analogous compounds in organic solvents.

The peptide rAc1-11 represents the dominant T cell epitope of rat myelin basic protein (MBP) in mice of the H-2u haplotype. Residue 4 has been shown previously to govern binding of the peptide to the class II molecule, I-Au. We have constructed peptide analogues bearing amino acid substitutions at position 4 and have assessed their ability to stimulate an antigen-specific T cell hybridoma when presented by viable antigen presenting cells (APC). Complexes between I-Au and one such analogue, rAc1-11[4A], were rapidly lost from the surface of live APC displaying a half-life (t 1/2) of approximately 10 min. Neither shedding of intact complexes from the cell surface, nor their internalization and recycling through an acidic intracellular compartment were found to account for their loss. The possible dissociation of rAc1-11[4A] from the peptide binding cleft was therefore addressed by comparing the t 1/2 of complexes between I-Au and peptide analogues of higher affinity. The tyrosine-substituted analogue, rAc1-11[4Y], remained stably bound to I-Au for at least 4 h, thereby displaying a t 1/2 far in excess of that evident for rAc1-11[4A]. Significantly, the wild type peptide, rAc1-11, bound so transiently that functional complexes could not be detected on the surface of peptide-pulsed APC. The physiological relevance of these findings was confirmed by extending our studies to an analysis of the homologous epitope of murine MBP; evidence that this epitope likewise displays minimal affinity for I-Au suggests a novel strategy for the escape from tolerance induction by encephalitogenic T cells.

The developmental anatomy of the ventricular outlets and intrapericardial arterial trunks is a source of considerable confusion. First, major problems exist because of the multiple names and definitions used to describe this region of the heart as it develops. Second, there is no agreement on the boundaries of the described components, nor on the number of ridges or cushions to be found dividing the outflow tract, and the pattern of their fusion.Evidence is also lacking concerning the role of the fused cushions relative to that of the so-called aortopulmonary septum in separating the intrapericardial components of the great arterial trunks. In this review, we discuss the existing problems, as we see them, in the context of developmental and postnatal morphology. We concentrate, in particular, on the changes in the nature of the wall of the outflow tract, which is initially myocardial throughout its length. Key features that, thus far, do not seem to have received appropriate attention are the origin, and mode of separation, of the intrapericardial portions of the arterial trunks, and the formation of the walls of the aortic and pulmonary valvar sinuses. Also as yet undetermined is the formation of the free-standing muscular subpulmonary infundibulum, the mechanism of its separation from the aortic valvar sinuses, and its differentiation, if any, from the muscular ventricular outlet septum.

—It is sometimes thought that formation of the atrioventricular septum is equated with fusion of the endocardial cushions and that failure of fusion can explain all deficiencies of atrioventricular septation. Clearly, this is simplistic, but the exact contribution of different primordia to atrioventricular septation is not well understood. To clarify this, we studied normal mouse embryos (days 10 to 15 of gestation), which were serially sectioned and examined by light microscopy. Another group of embryos was examined by scanning electron microscopy after microdissection. Our results show that development of the atrioventricular septal area is highly complex. Proper formation requires the following: remodeling of the inner heart curvature, rotation of the horns of the systemic venous sinus around the pulmonary portal, expansion of the right atrioventricular junction, formation of the muscular atrial and ventricular septa, bridging by the dextrodorsal outflow ridge and the superior endocardial cushion, fusion with the inferior margins of the venous valves, and formation of the mouth of the coronary sinus from the cranial muscular wall of the left sinus horn. Multiple primordia contribute to a central mesenchymal mass (the “septum intermedium”), including the mesenchyme on the leading edge of the primary atrial septum, the atrioventricular endocardial cushions, and the cap of mesenchyme on the spina vestibuli. Fusion of these components closes the ostium primum, completing atrial and atrioventricular septation. Additionally, the spina vestibuli has a mesodermal core, which contributes to the muscularization of the lower margin of the oval fossa. This contrasts with the formation of the upper rim, which occurs as a result of an infolding of the atrial wall itself.