© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Cardiac morphology at late fetal stages in the mouse with trisomy 16: consequences for different formation of the atrioventricular junction when compared to humans with trisomy 21
aDepartment of Anatomy & Developmental Biology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
bPaediatrics, Imperial College School of Medicine at National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK
* Corresponding author. Tel.: +44 (181) 725-2827; fax: +44 (181) 767-9109; e-mail: s.webb@sghms.ac.uk
Received 29 July 1996; accepted 4 February 1997
 |
Abstract |
|---|
 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Objective: The mouse with trisomy 16 (Ts16) is held to be a genetic model for humans with Down's syndrome (Ts21). Both trisomies are associated with atrioventricular septal defects, but the precise morphology in the mouse remains unclear. We have therefore characterised cardiac morphology in the mouse with Ts16. Methods: Ts16 fetuses, from a Rb(11.16)2H/Rb(16.17)7BnrxC57BL/6J cross, were collected on gestational days 17 or 18 (full term = 19 days) and studied using scanning electron microscopy and serial sections. Results: The hearts showed a spectrum of deficient atrioventricular septation which we categorised into two types. In one, a common atrioventricular junction was separated into right and left orifices by a tongue of tissue joining two valvar leaflets that bridged the ventricular septum to varying extent. In the other, a common atrioventricular junction was connected exclusively to the left ventricle. All hearts had ostium primum atrial and ventricular septal defects, together with abnormal ventriculo-arterial connections. No heart had the typical morphology seen in the human with Down's syndrome, namely a balanced common atrioventricular junction, guarded by a common valve, with the aorta connected exclusively to the left ventricle. Conclusions: The cardiac defects seen in Ts16 mice show marked differences from the typical anatomy in human Ts21, suggesting more complex mechanisms of cardiac dysmorphogenesis in Ts16. The mouse model will prove valuable in elucidating the mechanism of normal expansion of the atrioventricular junctions, and help in charting the precise steps involved in atrial and ventricular septation.
KEYWORDS Mouse; Atrioventricular septal defect; Heart; Trisomy; Down's syndrome; Animal model; Development
|
1 Introduction |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
The mouse with trisomy 16 (Ts16) has been proposed as a genetic model for human trisomy 21 (Down's syndrome) because murine chromosome 16 carries a number of markers and genes whose homologues map to human chromosome 21. Most of human chromosome 21q, thought to be the obligate region for Down's syndrome, is syntenic with mouse chromosome 16, except for a small telomeric portion which maps to mouse chromosomes 10 and 17 [1, 2]. Mouse chromosome 16, however, also has synteny with other human chromosomes, including 22q11 (a region implicated in DiGeorge syndrome), 16p and 3q [3–5].
The commonest cardiac malformation found in children with Down's syndrome is the consequence of deficient atrioventricular (AV) septation. Of all patients known to have trisomy 21 and a cardiac malformation, between 40% [6, 7] and 60% [8] have such deficient AV septation. In contrast, such atrioventricular septal defects (AVSD) are rare as an isolated lesion in the general population, representing only 2.8% of all congenital heart disease [8], although they are also common in patients having isomeric atrial appendages (visceral heterotaxy) [9]. Cardiovascular defects are common in mice with any trisomy, but characteristic patterns have been observed in only three. Pulmonary stenosis and double outlet right ventricle (DORV) accompany trisomy 13 [10, 11]; discordant ventriculo-arterial connections (‘transposition’) exist with trisomy 14 [10]; and AVSDs and malformations of the ventricular outflow tracts are caused by Ts16 [10, 12, 13]. Ts16 is unique, therefore, in that it is the only murine trisomy to show a high incidence of AVSDs.
In humans with Down's syndrome, the deficient AV septation is usually found in the setting of a common AV junction, guarded by a common valve, and with the junction more or less equally balanced between the ventricles [14]. In almost all cases, the aorta is exclusively connected within the left ventricle [15]. It has been established that the AV junctional arrangement is different in the Ts16 mouse, but the precise differences have yet to be emphasised. In addition, the trisomic mice tend also to have abnormal ventriculo-arterial connections, with both arterial trunks connected to the right ventricle, or with an overriding aorta, or else to have a common arterial trunk [12, 13, 16].
These different arrangements at both the AV and ventriculo-arterial junctions when compared to human malformations must be the result of disparate morphogenesis. If this is the case, this would have obvious implications for the use of the mouse with Ts16 as a developmental model for the human situation. This possibility was not considered in previous studies of the hearts from mice with Ts16 [13, 17], since these studies were not specifically designed to make comparison with the cardiac defects known to be associated with Down's syndrome. To clarify the situation, we have studied a large series of hearts from mice with Ts16 close to term, using scanning electron microscopy (SEM) and serial histological sections. Our findings have revealed marked differences from the typical intracardiac morphology encountered in humans with Down's syndrome.
|
2 Methods |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
2.1 Animals
Mice with Ts16 were generated by mating doubly heterozygous Rb(11.16)2H/Rb(16.17)7Bnr males overnight with C57BL/6J females (an all-acrocentric stock). The presence of a copulation plug the next morning was taken as evidence of successful mating, and this day was designated the first day of gestation. Pregnant dams were sacrificed by cervical dislocation on the 17th or 18th day of gestation (full term=19 days). The conceptuses were explanted and the extra-embryonic membranes removed. Each fetus was examined under a binocular dissecting microscope for morphologic evidence of trisomy. A minority of fetuses were found to have characteristic oedema of the neck and back, subcutaneous haematomas, hypoplasia of the thymus gland, and open eyes (the eye-lids being closed in disomic mice at this stage of gestation). In our previous studies, and as shown elsewhere [18], these phenotypic features are consistently associated with Ts16 in the mouse. All mice with this phenotype in our study showed evidence of deficient AV septation. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985).
2.2 Scanning electron microscopy
Microdissection of fetal hearts was performed under a stereomicroscope, using watchmakers' forceps and iridectomy scissors. Prior to dissection, each heart was perfused through the inferior caval vein, first with saline, and then with fixative (2% gluteraldehyde, 1% formaldehyde in 0.5 M cacodylate buffer, pH 7.4, osmotically adjusted to 330 mOsm with NaCl). Our technique is a modification of the system producing fixation at high flow and low pressure devised by Pexeider [19]. Perfusion was followed by immersion overnight in fixative at room temperature. Where possible, hearts were left attached to the thoracic wall during processing to ensure optimal preservation of cardiac architecture. All samples were post-fixed in 1% osmium tetroxide, dehydrated through a series of graded alcohols, critical-point-dried using liquid carbon dioxide as the transition fluid, then sputter-coated with 240 Å gold. Samples were viewed on a Zeiss SM940 scanning electron microscope at 25 kV. A total of 43 hearts from trisomic fetuses were viewed by SEM in this study, and compared with results from 38 normal hearts processed in similar fashion. The findings in the normal hearts have been the focus of a comprehensive study of cardiac anatomy in the mouse, published elsewhere [20].
2.3 Serial sections
In addition to the 81 hearts processed for SEM, hearts from 12 trisomic and 8 normal embryos, selected at random, were prepared for light microscopic examination. Initial fixation was as described for SEM, using a mixture of 40% acetone/40% methanol/20% distilled water as fixative. This was followed by overnight immersion fixation at room temperature. After fixation, the embryos were rinsed, dehydrated through a series of graded alcohols, embedded in paraffin wax and serially sectioned at a nominal thickness of 7 µm using a rotary microtome. Sections were dewaxed, rehydrated, and stained with Masson's trichrome stain. The sections were dehydrated and coverslipped using DPX mounting medium. Micrographs of the sections were taken using a Zeiss D-7082 transmitted-light stereo photomicroscope.
|
3 Results |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
The AV junctional arrangement was as expected in all normal embryos (Fig. 1A), but abnormal in all the fetuses examined with the phenotypic features of Ts16. There was a spectrum in the degree to which the AV junction was connected to the left and right ventricles. We were able to categorise these different AV junctional arrangements into two patterns. In the first, seen in 22 of the 43 hearts studied by SEM (Table 1), the AV junction was connected in part to both the left and right ventricles (Fig. 1B). This common junction was guarded by a valve with superior and inferior leaflets that bridged the crest of the ventricular septum (Fig. 2F and Fig. 3B). A tongue of valvar tissue joined together the bridging leaflets, so as to divide the common junction into separate right and left AV valvar orifices (arrow in Fig. 1B). Each valvar orifice was connected to a separate ventricle. Despite the fusion of the leaflets, the superior bridging leaflet was free and distant from the ventricular septum, roofing the defect between left and right ventricles (Fig. 3B). The connection of the common junction within the right ventricle was appreciable (Fig. 1B) in 10 of these hearts, with the right AV valvar orifice approaching the size of the left. In the 12 other hearts, the connection to the right ventricle was less extensive, with only a small slit-like orifice being seen in the most extreme cases (Fig. 1C).
|
). Panel D shows a specimen with a junction exclusively committed to the left ventricle, but with an imperforate pit in the floor of the right atrium (arrowed). Scale bars = 200 µm.
|
|
|
In the remaining 21 hearts, the common AV junction was connected exclusively to the left ventricle (Fig. 1D, Fig. 2D and Fig. 5E,F). The valve guarding the common junction in this setting had inferior and superior leaflets (Fig. 3A), and often a small mural leaflet. The inferior leaflet was firmly fused to the crest of the ventricular septum in 10 of the 21 hearts, but in these 10 specimens the superior leaflets ‘floated’ clear of the ventricular septum to form the roof of an extensive ventricular septal defect which was overridden by the aortic orifice. In the other 11 hearts, both leaflets were fused to the crest of the ventricular septum. Because the atrial chambers were connected only to the left ventricle, there was no direct inlet to the right ventricle via the AV junction (Fig. 2C,D and Fig. 3A), with the muscular floor of the right atrium overlaying the right AV groove (Fig. 1D). In all hearts, therefore, the connection between the ventricles was through a ventricular septal defect. This defect extended to become continuous with the outflow tract of the overriding aorta in 10 hearts, but in the remaining 11 hearts it had exclusively muscular borders.
|
Within the overall series, no heart examined had the aorta connected exclusively in the left ventricle. Instead, in 22 cases there was a double outlet from the right ventricle (Fig. 2D,F, Fig. 3A,B and Fig. 4A) and, in 18 cases, overriding of the ventricular septum by the aorta (Fig. 2E and Fig. 4B). A common arterial trunk was observed in two hearts, with discordant ventriculo-arterial connections being seen in the remaining heart (Table 1). In some hearts with a double outlet from the right ventricle, the adjacent leaflets of the aortic and pulmonary valves were themselves in fibrous continuity (small arrow in Fig. 4A). In these cases, there was absence of a complete muscular infundibulum beneath the pulmonary valve, together with absence of any muscular outlet septum (contrast Fig. 4A,B).
|
The communication between the right and left atria was through an ostium primum defect in all the hearts from fetuses with phenotypic characteristics of Ts16 (Fig. 2B,E and Fig. 3A,B). This is in contrast to the communication across the oval foramen which occurs in the normal fetal heart. All hearts examined also had a ventricular septal defect. In those hearts with the AV junction connected exclusively to the left ventricle, this was the only route of blood to the right ventricle. In those hearts with DORV, the ventricular septal defect was the only route for outflow from the left ventricle. The ventricular septal defect either had exclusively muscular borders (Fig. 4B), or else was overridden by the aortic valve, with its leaflets in fibrous continuity with the superior bridging leaflet of the AV valve (Fig. 3A,B).
The serial histological sections (Fig. 5) confirmed the findings described from SEM observations. Hearts were shown to have either a divided common junction, shared to various extents between the ventricles, with a floating superior bridging leaflet, (Fig. 5A–C), or else a common junction connected exclusively to the left ventricle (Fig. 5D–F). The ventricular septal defect feeding the right ventricle then had either exclusively muscular borders or else was overridden by the leaflets of the aortic valve in continuity with the superior bridging leaflet.
|
4 Discussion |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
The purpose of our study was to compare the morphology of the heart in murine Ts16 with the known cardiac defects associated with Down's syndrome in the human [6, 7, 21]. In the past, it has been implied [12, 13, 16] that the cardiac lesions in the two trisomies are comparable. It is certainly true that there is deficient AV septation in both settings, and that the patterns seen in the mouse can sometimes be found in humans. It is misleading, however, to consider the murine anatomy as providing a model of the cardiac phenotype seen in Down's syndrome. It may be helpful if we begin by emphasising the nature of deficient AV septation as seen in humans when their septal abnormality co-exists with a common AV junction, morphology which is comparable irrespective of the presence of Down's syndrome. The arrangement is usually classified as ‘complete’ when there is a common AV valvar orifice, or ‘partial’ (so-called ostium primum defect) when the common AV junction is divided into separate valvar orifices for the right and left ventricles. So-called ‘partial’ defects are rare in humans with Down's syndrome. The AV junctional morphology of these two variants, however, is virtually identical [15]. The AV junctions, by definition, are those areas in which atrial myocardium is contiguous with ventricular myocardium (albeit separated by fibrous insulating tissues). Junctional morphology is independent of, and needs to be analysed separately from, the morphology of the AV valves, in particular the locus of the hingepoints of their leaflets.
In humans with Down's syndrome, as emphasised above, the majority of patients not only have a common AV junction, but they also have a common valvar orifice, in other words the so-called ‘complete’ variant [21]. None of the Ts16 mouse hearts in our study had this morphologic pattern, namely a common junction guarded by a common valve. Furthermore, none of the mice had another feature expected in humans with Down's syndrome and AVSD, namely the aorta connected exclusively within the left ventricle. There are then further significant areas of difference between the typical patterns observed in mice as compared to humans. These reflect, first, the degree of connection of the AV junction to the right ventricle; second, the nature of septation of the outflow tract; and, third, the extent of atrial septation. Each of these features has been illustrated in previous studies [13, 16, 17]. What has not been emphasised is that the typical overall arrangement seen in the Ts16 mouse is markedly different from the usual pattern of deficient AV septation seen in humans with trisomy 21 and common AV junction.
The morphology of the cardiac lesions seen in the trisomic mice themselves could be divided into two types. In the first, the AV junction is exclusively connected to the left ventricle. In the other, the common junction is connected to both ventricles via separate AV valves, but with the connection in the right ventricle ranging from minimal to almost balanced. It is very likely that all the hearts form part of a continuum, ranging from exclusively left to almost balanced connections. This strongly suggests that the trisomic mice exhibit a major developmental defect in the alignment of the cardiac chambers. Such malalignment, in contrast, is rare in humans with Down's syndrome and AVSD, almost all having balanced connection of the common AV junction to left and right ventricles [14]. Indeed, the finding of the unbalanced variant of AVSD in humans is much commoner in patients with normal chromosomes.
We propose, therefore, that, in addition to deficient AV septation, mice with Ts16 are also defective in the morphogenetic processes that remould the inner curvature of the heart tube so as to align normally the outlet portion of the ventricular loop with the right side of the primary atrium, thus establishing the right AV connection. In support of this, we have observed that the ventricular loop of Ts16 embryos already has an abnormal architecture on the 10th day of development [22]. In addition, similar looping defects have been noted in some iv/iv mouse embryos, with an AVSD being seen in a proportion of these fetuses [23].
In addition to these looping defects, Ts16 hearts also have abnormalities in development of the AV endocardial cushions. We, and others, have shown defects in volumes of and numbers of mesenchymal cells in the cushions in Ts16 [13, 22, 24]. It is tempting to speculate that the abnormalities of the cushions in Ts16 are part and parcel of the steps leading to formation of AVSD with common junction, as seen also in humans with Down's syndrome. This may be caused by a common dosage effect of gene(s) in the region syntenic between human chromosome 21 and mouse chromosome 16. If it is true that the cushions form a large part of the valvar leaflets, however, it is difficult to reconcile the fact that, in the mice, the bridging leaflets were attached to each other with the notion that the lesion exists because of failure of fusion of the endocardial cushions. Irrespective of this conundrum, the abnormality in looping (and the abnormal septation) may be caused by trisomy of gene(s) on mouse chromosome 16 that have no synteny with human chromosome 21. Candidate genes may be those in the human DiGeorge region (22q11) which also map to mouse chromosome 16 [4, 5].
The defects of the outflow tract, and the nature of abnormal atrial septation seen in Ts16, have certainly been reported previously [13, 16, 17]. It is likely that the outflow defects, with either aortic overriding or double outlet seen in most cases, are also related to looping abnormalities, pointing again to the significance of moulding of the inner heart curvature. We agree with previous suggestions that they are reminiscent of DiGeorge syndrome [16]. These types of defects can also sometimes be seen in humans with Down's syndrome and AV septal defect, notably in the association with tetralogy of Fallot [21]. The abnormal atrial septation in the mice with Ts16 was also previously observed [13, 17]. It has been suggested [25] that this is due to absence of, or diminution in, the contribution made from the extracardiac mesoderm (the ‘spina vestibuli’ of His [26]).
Although not necessarily being comparable to typical AVSD in humans, the findings in some of the Ts16 hearts do bear resemblance to other known human cardiac malformations. In those with exclusive AV connection to the left ventricle, the arrangement of the floor of the right atrium is reminiscent of so-called tricuspid atresia [27]. In those with the common junction shared between the ventricles, the arrangement is similar to that in the human described as AV septal defect with left ventricular dominance [14]. The pattern with overriding aorta is comparable to AVSD with tetralogy of Fallot. In the overall spectrum of AVSD as seen in the human, however, these variants are very much the exceptions rather than the rule.
In conclusion, we have demonstrated marked differences between the cardiac morphology of murine Ts16 and humans with Down's syndrome. The fundamental difference is in the connections of the AV and ventriculo-arterial junctions to the ventricular mass, suggesting a profound defect of segmental alignment in Ts16 that is not seen in human's with Down's syndrome. Ts16 in the mouse, therefore, provides a unique model in which to study the development of the inner curvature of the heart loop. It should also prove valuable in determining the contribution to the septal structures from the extracardiac mesenchyme. The disparities in cardiac morphology we have described, however, in no way diminish the likelihood that the two trisomies share the genetic consequences of having three copies of the genes within the syntenic region. Rather, they emphasise that, in the mouse, this may be complicated by trisomy outside the syntenic region.
Time for primary review 30 days.
|
Acknowledgements |
|---|
We wish to thank I.D. Harragan and R.F. Moss for technical assistance. This study was supported by the British Heart Foundation and the UK Medical Research Council.
|
References |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Nadeau J. Maps of linkage and synteny homologies between mouse and man. Trends Genet (1989) 5:82–86.[CrossRef][Web of Science][Medline]
- Lyon M.F., Kirby M.C. Mouse chromosome atlas. Mouse Genome (1995) 93:23–66.
- Wilson D.I., Cross I.E., Goodship J.A., et al. A prospective cytogenetic study of 36 cases of DiGeorge syndrome. Am J Hum Genet (1992) 51:957–963.[Web of Science][Medline]
- Carey A.H., Kelly D., Halford S., et al. Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. Am J Hum Genet (1992) 51:964–970.[Web of Science][Medline]
- Driscoll D.A., Budarf M.L., Emanuel B.S. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet (1992) 50:924–933.[Web of Science][Medline]
- Rowe R.D., Uchida I.A. Cardiac malformation in mongolism. Am J Med (1961) 31:726–735.[CrossRef][Web of Science][Medline]
- Park S.C., Mathews R.A., Zuberbuhler J.R., Rowe R.D., Neches W.H., Lenox C.C. Down syndrome with congenital heart malformation. Am J Dis Child (1977) 131:29–33.
[Abstract/Free Full Text] - Ferencz C., Neill C.A., Boughman J.A., Rubin J.D., Brenner J.I., Perry L.W. Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J Pediatr (1989) 114:79–86.[CrossRef][Web of Science][Medline]
- Icardo J.M., Sanchez de Vega M.J. Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy. Circulation (1991) 84:2547–2558.
[Abstract/Free Full Text] - Pexieder T, Miyabara S, Gropp A. Congenital heart disease in experimental (fetal) mouse trisomies: incidence. In: Pexieder T, editor. Perspectives in cardiovascular research, vol. 5. New York: Raven Press, 1981:389–399.
- Vuillemin M., Pexieder T., Winking H. Pathogenesis of various forms of double outlet right ventricle in mouse fetal trisomy 13. Int J Cardiol (1991) 33:281–304.[CrossRef][Web of Science][Medline]
- Miyabara S., Gropp A., Winking H. Trisomy 16 in the mouse fetus associated with generalized edema and cardiovascular and urinary tract anomalies. Teratology (1982) 25:369–380.[CrossRef][Web of Science][Medline]
- Miyabara S. Cardiovascular malformations of mouse trisomy 16: pathogenetic evaluation as an animal model for human trisomy 21. In: Clark EB, Takao A, editors. Developmental cardiology: morphogenesis and function. Mount Kisco, NY: Futura Publishing Co. 1990:409–430.
- Bharati S., Lev M. The spectrum of common atrioventricular orifice (canal). Am Heart J (1973) 86:553–561.[CrossRef][Web of Science][Medline]
- Anderson R.H., Baker E.J., Ho S.Y., Rigby M.L., Ebels T. The morphology and diagnosis of atrioventricular septal defects. Cardiol Young (1991) 1:290–303.
- Miyabara S. Animal model for congenital anomalies induced by chromosome aberrations. Congen Anom (1990) 30:49–68.
- Miyabara S., Sugihara H., Yonemitsu N., Yun K. Comparative study of phenotypic expression of mice trisomy 16 by different female strains: attempt at an animal model for human trisomy 21. Congen Anom (1984) 24:283–292.
- Epstein D.J., Vekemans M. Genetic control of the survival of murine trisomy 16 fetuses. Teratology (1990) 42:571–580.[CrossRef][Web of Science][Medline]
- Pexieder T. Prenatal development of the endocardium: a review. Scanning Electron Microscopy 1981;II:223–253.
- Webb S., Brown N.A., Anderson R.H. The structure of the mouse heart in late fetal stages. Anat Embryol (1996) 194:37–47.[Medline]
- Marino B., Vairo U., Corno A., et al. Atrioventricular canal in Down syndrome. Prevalence of associated cardiac malformations compared with patients without Down syndrome. Am J Dis Child (1990) 144:1120–1122.
[Abstract/Free Full Text] - Webb S., Anderson R.H., Brown N.A. Endocardial cushion development and heart loop architecture in the trisomy 16 mouse. Dev Dyn (1996) 206:301–309.[CrossRef][Web of Science][Medline]
- Seo J., Brown N.A., Anderson R.H. Abnormal laterality and congenital cardiac anomalies. Relations of visceral and cardiac morphologies in the iv/iv mouse. Circulation (1992) 86:642–650.
[Abstract/Free Full Text] - Hiltgen G.G., Markwald R.R., Litke L.L. Morphogenetic alterations during endocardial cushion development in the trisomy 16 (Down syndrome) mouse. Pediatr Cardiol (1996) 17:21–30.[Web of Science][Medline]
- Asami I, Koizumi K. Development of the atrial septal complex in the human heart: contribution of the spina vestibuli. In: Clark EB, Markwald RR, Takao A, editors. Developmental mechanisms of heart disease. New York: Futura Publishing Company, Inc. 1995:255–260.
- His W. Die Area interposita, die Eustachi'sche Klappe und die Spina vestibuli. In: Anatomie menschlicher Embryonen. Leipzig: Verlag von F.C.W. Vogel, 1880:149–152.
- Scalia D., Russo P., Anderson R.H., et al. The surgical anatomy of hearts with no direct communication between the right atrium and the ventricular mass–so-called tricuspid atresia. J Thorac Cardiovasc Surg (1984) 87:743–755.[Abstract]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. N. Bekker, N. M. S. van den Akker, M. M. Bartelings, J. B. Arkesteijn, S. G. L. Fischer, J. A. E. Polman, M. C. Haak, S. Webb, R. E. Poelmann, J. M. G. van Vugt, et al. Nuchal Edema and Venous-Lymphatic Phenotype Disturbance in Human Fetuses and Mouse Embryos With Aneuploidy Reproductive Sciences, April 1, 2006; 13(3): 209 - 216. [Abstract] [PDF]
|
|
|
|
 |
|
 P. J. Gruber and J. A. Epstein Development Gone Awry: Congenital Heart Disease Circ. Res., February 20, 2004; 94(3): 273 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Jiao, H. Kulessa, K. Tompkins, Y. Zhou, L. Batts, H. S. Baldwin, and B. L.M. Hogan An essential role of Bmp4 in the atrioventricular septation of the mouse heart Genes & Dev., October 1, 2003; 17(19): 2362 - 2367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Bartram, D. G. M. Molin, L. J. Wisse, A. Mohamad, L. P. Sanford, T. Doetschman, C. P. Speer, R. E. Poelmann, and A. C. Gittenberger-de Groot Double-Outlet Right Ventricle and Overriding Tricuspid Valve Reflect Disturbances of Looping, Myocardialization, Endocardial Cushion Differentiation, and Apoptosis in TGF-{beta}2-Knockout Mice Circulation, June 5, 2001; 103(22): 2745 - 2752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kirchhoff, J.-S. Kim, A. Hagendorff, E. Thonnissen, O. Kruger, W. H. Lamers, and K. Willecke Abnormal Cardiac Conduction and Morphogenesis in Connexin40 and Connexin43 Double-Deficient Mice Circ. Res., September 1, 2000; 87(5): 399 - 405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Webb, R. H. Anderson, W. H. Lamers, and N. A. Brown Mechanisms of Deficient Cardiac Septation in the Mouse With Trisomy 16 Circ. Res., April 30, 1999; 84(8): 897 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H Anderson, S. Webb, and N. A Brown The mouse with trisomy 16 as a model of human hearts with common atrioventricular junction Cardiovasc Res, July 1, 1998; 39(1): 155 - 164. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||