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Results for “Truncus Arteriosus, Persistent”

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PubMed1995

Platelet-derived growth factor receptor alpha subunit deleted Patch mouse exhibits severe cardiovascular dysmorphogenesis.

Patch (Ph) mice, whose platelet-derived growth factor receptor alpha subunit (alpha PDGFR) gene has been deleted, have been used to elucidate requirements for alpha PDGFR for normal murine development. In this report we evaluate the role of alpha PDGFR in cardiovascular development by using in situ hybridization to follow the changing pattern of alpha PDGFR expression in cardiovascular tissues after embryonic day 13, and comparing this pattern with the pattern of cardiovascular defects observed in homozygous Ph mutants. Both mesodermally derived and neural crest-derived components of the cardiovascular system are severely dysmorphic in Ph/Ph embryos and those structures most severely affected are those that normally express alpha PDGFR mRNA at the highest levels and for the longest duration. Ph/Ph vessels appear to be lined with a normal endothelium, but contain a reduced number of smooth muscle cells and are fragile during processing for histology. The myocardium is thin, the heart is small and dysmorphic, the valves are malformed, and the interventricular and interatrial septa of the heart are defective. In the outflow tract, the spectrum of defects includes both persistent truncus arteriosus and double outlet right ventricle. This pattern of abnormalities is consistent with the hypothesis that deletion of alpha PDGFR results in a functional ablation of cranial neural crest cells, and that mesodermally derived components of the vascular system also require alpha PDGFR.

Animals↗

PubMed1998

Alterations of myocardial contraction associated with a structural heart defect in embryonic chicks.

Ablation of cardiac neural crest at stages 8-10 produces a structural heart defect (persistent truncus arteriosus, PTA) in embryonic chicks. PTA is associated with decreased myocardial contractility, as indicated by decreased left ventricular ejection fraction. We compared the force of small ventricular strips from normal and defective chick hearts. In intact muscle, ablation of the neural crest leads to a 30-50% decrease in twitch force at any level of extracellular Ca2+ (0.45-20 mM) at embryonic days (ED) 7 and 15, relative to sham-operated controls. These differences could reflect defects at the level of the contractile apparatus and/or in the excitation-contraction coupling process. To distinguish changes of the contractile apparatus, we used detergent skinned preparations. The maximal Ca(2+)-activated force (Fmax) at ED15 was not significantly different between control and experimental embryos. At ED 7, however, Fmax was reduced by 36% in experimental preparations. Electron-micrographs showed that the organization and orientation of the myofibrils was similar in experimental and control ventricles. At ED 14, however, the average myofibrillar diameter was significantly increased in experimental ventricles. The content of the major myofibrillar proteins (myosin heavy chain, actin, and tropomyosin), determined from polyacrylamide gel electrophoresis and Coomassie Blue staining, normalized to total protein, was not statistically different in experimental and control ventricles at ED7. At ED15, however, content of these proteins was doubled in experimental ventricles. These data suggest a possible defect of the contractile apparatus at both ED 7 and 15, since the ratio of Fmax/myosin is reduced in the experimental hearts.

Animals↗

PubMed1999

Excessive microtubules are not responsible for depressed force per cross-bridge in cardiac neural-crest-ablated embryonic chick hearts.

Ablation of the cardiac neural crest (CNCA) in embryonic chicks results in a high incidence of persistent truncus arteriosus, a congenital heart defect associated with decreased myocardial contractility. Using left ventricular trabeculae from chicks at embryonic day (ED) 15, we have previously shown that the twitch force of intact preparations is significantly reduced whereas the maximal calcium-activated force of skinned preparations is not significantly different in CNCA and sham-operated animals. We also previously found that the ventricular content of myosin, as well as of actin and tropomyosin, was nearly doubled in ED 15 hearts after CNCA. Since the number of cross-bridges is proportional to the myosin concentration, these data suggest that the force exerted per cross-bridge is decreased in CNCA hearts. We investigated the possibility that the decrease in force per cross-bridge is caused by inhibition of the contractile apparatus by excessive microtubules. To the contrary, we found that the total beta-tubulin content and the fraction of beta-tubulin polymerized in microtubules measured by Western blotting was the same in ventricular muscle strips from CNCA and sham-operated embryos. Furthermore, exposure to microtubule-destabilizing agents did not improve the force-producing capability of the contractile apparatus in CNCA embryos. We conclude that depression of force per cross-bridge in hearts from CNCA embryos is not due to an excess of microtubules.

Animals↗

PubMed2005

The keeshond defect in cardiac conotruncal development is oligogenic.

Earlier studies in the keeshond breed of dogs established that isolated conotruncal defects (CTDs) are a group of genetically and embryologically related cardiac malformations, including sub-clinical defects of the conal septum, conal ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. The same spectrum occurs in some human families. In both species, inheritance of non-syndromic CTDs is usually complex and multifactorial inheritance has been assumed. Previous studies in the keeshond suggested that susceptibility to CTD is an autosomal recessive trait, with alleles at modifying loci affecting severity. Here we report results of a genome-wide scan for CTD linked loci in a keeshond x beagle F1 backcross pedigree in which 46 of 101 offspring had CTDs. Two-point linkage analysis identified regions of suggestive linkage on each of three chromosomes CFA2, CFA9, and CFA15. No single locus accounted for segregation of CTDs in the pedigree, ruling out a single autosomal susceptibility locus. Multipoint analysis with Genehunter resulted in a corrected LOD score of 3.7 at the locus on CFA9 and supported linkage to the loci on CFA2 and CFA15 (LOD scores of 2.71 and 3.03). Genehunter Twolocus analysis suggested that CTD-predisposing alleles of these three loci are necessary, at least in pairs, to produce CTD. The canine CTD-linked chromosome regions are orthologous to human regions HSA5q11-13, HSA5q31, HSA17q11-24, and HSA4q31. We excluded from the linked regions in the dog, a number of genes known to have a role in the etiology of CTDs and predict that continuing studies will identify CTD-predisposing genes not previously recognized.

Animals↗

PubMed1980

Crossed atrioventricular connections.

Four cases of crossed atrioventricular connections are described. All of them were diagnosed at cardiac catheterization by angiocardiography and one was examined pathologically. Two possessed situs solitus, one with concordant connections and the other with discordant connections; the other had two situs inversus, both of them with concordant connections. Two had double-outlet right ventricle, one had transposition of the great arteries, and the other had normally related and connected great arteries. These cases have been interpreted as representing abnormal rotation of the ventricles following sepatation. A review of 36 cases previously reported on and our own cases, suggests that most patients have concordant atrioventricular connections. There are many types of ventriculo-arterial connections, the most frequent being transposition of the great arteries. There has not been any case reported with persistent truncus arteriosus. On the basis of atrioventriculo-arterial connections, we propose a classification for this malformation. We discuss the importance of the bulboventricular loop in the type of atrioventricular connections, some clinical implications for the diagnosis, and analyze the value of the rules to localize the ventricles by means of the position of the great arteries.

Adolescent↗

PubMed1987

Anatomy and pathogenesis of aorticopulmonary septal defect.

The pathologic anatomic features and associated cardiac anomalies of 13 patients with aorticopulmonary septal defect (APSD) and of 236 previously reported cases were analyzed. Morphologically, 3 types of APSD were distinguished: a defect with a more or less circular border located about halfway between the arterial valves and the bifurcation of the pulmonary trunk; a similarly located defect in which the border represents a helix; and a usually large defect in which there is no posterior (distal) border. The appearance of these 3 types of defects suggests a different developmental mechanism for each. Approximately half of the cases of APSD are not associated with other cardiovascular anomalies. Of the anomalies that do occur, anomalous origin of a coronary artery from the pulmonary trunk and interruption of the aortic arch (IAA) type A or severe preductal coarctation are seen far more often than expected. An association with DiGeorge syndrome, frequently noted with persistent truncus arteriosus (TA) and IAA type B, was not seen. Certain cardiac anomalies often seen with TA are rarely seen with APSD, and defects often seen with APSD are rarely seen with TA. These observations indicate that APSD and TA are pathogenetically unrelated even though located in the same region of the heart and, unlike TA and IAA type B, APSD is probably not due to a developmental error involving the neural crest.

Aortopulmonary Septal Defect↗

PubMed1989

Plasticity and predetermination of mesencephalic and trunk neural crest transplanted into the region of the cardiac neural crest.

The cardiac neural crest contains ectomesenchymal and neural anlagen that are necessary for normal heart development. It is not known whether other regions of the neural crest are capable of supporting normal heart development. In the experiments reported herein, quail donor embryos provided cardiac, trunk, or mesencephalic neural crest to replace or add to the chick host cardiac neural crest. Neither trunk nor mesencephalic neural crest was capable of generating ectomesenchyme competent to effect truncal septation. Addition of mesencephalic neural crest resulted in a high incidence of persistent truncus arteriosus, suggesting that ectomesenchyme derived from the mesencephalic region interferes with ectomesenchyme derived from the cardiac neural crest. Derivatives from the trunk neural crest, on the other hand, did not result in abnormal development of the truncal septum. While mesencephalic neural crest seeded the cardiac ganglia with both neurons and supporting cells, this capability was limited in the trunk neural crest to the more mature regions. These studies indicate a predetermination of the ectomesenchymal derivatives of the cranial neural crest and a possible competition of neural anlagen to form neurons and supporting cells in the cardiac ganglia.

Animals↗

PubMed2004

Primary repair for aortic arch obstruction associated with ventricular septal defect.

BACKGROUND: The aim of the present study was to evaluate the current outcome and reoperation rate after applying a one-stage correction strategy for interrupted aortic arch (IAA) with ventricular septal defect (VSD) and also for aortic coarctation and hypoplastic aortic arch (CoA-HyAA) with VSD beginning September 1999. METHODS: Twenty-four consecutive patients with IAA (n = 12) or CoA-HyAA (n = 12) with VSD underwent early one-stage correction. Patients' mean age was 12 days (range, 2 to 188); mean weight was 3.6 kg (range, 2.1 to 7.3), 6 patients were less than 2.5 kg. Three IAA were type A, 5 type B1, 3 type B2, and 1 type C. Associated anomalies included a large VSD in all, left ventricular outlet tract obstruction in 5, transposition of the great arteries, aortopulmonary window, persistent truncus arteriosus, and double-outlet right ventricle in 1 patient. Selective brain perfusion through innominate artery and selective coronary perfusion through aortic root during aortic arch reconstruction was used in all patients. Mean follow-up was 2.2 +/- 0.9 years. RESULTS: There was no early, no late mortality, and no postoperative neurologic complications. Mean crossclamp duration was 72 +/- 32 minutes, lowest temperature 22.8 +/- 4 degrees C and selective brain and coronary perfusion duration was 34 +/- 13 minutes. Eighteen patients required delayed sternal closure at 1.7 days postoperatively. New perioperative management reduced the overall morbidity. Four patients after IAA plus VSD repair developed aortic arch restenosis and were successfully treated by balloon dilatation. One patient with d-TGA underwent right ventricular outflow tract reconstruction of right ventricular outlet tract obstruction 7 months after the initial repair. Pressure gradients across the anastomosis at most recent follow up were less than 10 mm Hg. All patients are asymptomatic and are developing normally. CONCLUSIONS: One-stage complete correction is feasible in newborns with aortic arch obstruction with VSD. Complex cardiac anatomy presents no additional risk for the procedure. The early one-stage correction yields excellent surgical results and good functional outcome.

Aorta, Thoracic↗

PubMed2005

Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFbeta receptor (Tgfbr2) mutant mice.

Previous studies have demonstrated that TGFbeta induces a smooth muscle fate in primary neural crest cells in culture. By crossing a conditional allele of the type II TGFbeta receptor with the neural crest-specific Wnt1cre transgene, we have addressed the in vivo requirement for TGFbeta signaling in smooth muscle specification and differentiation. We find that elimination of the TGFbeta receptor does not alter neural crest cell specification to a smooth muscle fate in the cranial or cardiac domains, and that a smooth muscle fate is not realized by trunk neural crest cells in either control or mutant embryos. Instead, mutant embryos exhibit with complete penetrance two very specific and mechanistically distinct cardiovascular malformations--persistent truncus arteriosus (PTA) and interrupted aortic arch (IAA-B). Pharyngeal organ defects such as those seen in models of DiGeorge syndrome were not observed, arguing against an early perturbation of the cardiac neural crest cell lineage. We infer that TGFbeta is an essential morphogenic signal for the neural crest cell lineage in specific aspects of cardiovascular development, although one that is not required for smooth muscle differentiation.

Alleles↗

PubMed2006

N-cadherin is required for neural crest remodeling of the cardiac outflow tract.

Cardiac neural crest cells undergo extensive cell rearrangements during the formation of the aorticopulmonary septum in the outflow tract. However, the morphogenetic mechanisms involved in this fundamental process remain poorly understood. To determine the function of the Ca2+-dependent cell adhesion molecule, N-cadherin, in murine neural crest, we applied the Cre/loxP system and created mouse embryos genetically mosaic for N-cadherin. Specifically, deletion of N-cadherin in neural crest cells led to embryonic lethality with distinct cardiovascular defects. Neural crest cell migration and homing to the cardiac outflow tract niche were unaffected by loss of N-cadherin. However, N-cadherin-deficient neural crest cells were unable to undergo the normal morphogenetic changes associated with outflow tract remodeling, resulting in persistent truncus arteriosus in the majority of mutant embryos. Other mutant embryos initiated aorticopulmonary septum formation; however, the neural crest cells were unable to elongate and align properly along the midline and remained rounded with limited contact with their neighbors. Interestingly, rotation of the outflow tract was incomplete in these mutants suggesting that alignment of the channels is dependent on N-cadherin-generated cytoskeletal forces. A second cardiac phenotype was observed where loss of N-cadherin in the epicardium led to disruption of heterotypic cell interactions between the epicardium and myocardium resulting in a thinned ventricular myocardium. Thus, we conclude that in addition to its role in myocardial cell adhesion, N-cadherin is required for neural crest cell rearrangements critical for patterning of the cardiac outflow tract and in the maintenance of epicardial-myocardial cell interactions.

Animals↗

PubMed2002

Requirement for AP-2alpha in cardiac outflow tract morphogenesis.

Most developing structures that express the transcription factor gene AP-2alpha are compromised in AP-2alpha mutant mouse embryos. Since the cardiac neural crest population is one prominent site of AP-2alpha expression, and because the neural crest is known to be required for normal cardiac morphogenesis, we have investigated the involvement of AP-2alpha in cardiac development. All AP-2alpha-deficient embryos examined had malformations of the outflow tract of the developing heart: most had double outlet right ventricle, and a small fraction had persistent truncus arteriosus. To visualize AP-2alpha-expressing cells during the period of cardiac morphogenesis, we established a new mutant germline allele in which an IRES-lacZ sequence was inserted by homologous recombination into the AP-2alpha locus. Positive expression was observed in the cardiac neural crest population during the E9.5-10.5 period (as well as in other known domains of AP-2alpha expression previously noted by in situ hybridization studies), and was mostly extinguished by E11.5 when the cardiac neural crest has migrated into the outflow tract of the developing heart. Importantly, the distribution of AP-2alpha-expressing cardiac neural crest appeared to be identical in normal and mutant embryos. From this analysis, we propose that the AP-2alpha gene functions within the neural crest lineage, that AP-2alpha is not required for neural crest cell migration, and that normal AP-2alpha gene function is required prior to E11.5. AP-2alpha may be involved in an interaction between neural crest and surrounding tissues in the subpharyngeal region, thereby promoting normal outflow tract morphogenesis.

Animals↗

PubMed2003

The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases.

Pitx2 is a bicoid-related homeodomain transcription factor that plays a critical role in directing cardiac asymmetric morphogenesis. Ectopic Pitx2c expression in the developing myocardium correlates with double outlet right ventricle (DORV) in laterality mutants. Pitx2 loss of function experiments cause severe cardiovascular defects, such as atrial isomerism (AI), double inlet left ventricle, transposition of the great arteries (TGA), persistent truncus arteriosus (PTA), and abnormal aortic arch (AAA) remodeling. Current studies suggest that Pitx2-mediated signaling during cardiogenesis is conducted within three different cell types: the myocardium, the cardiac neural crest (CNC) cells, and the pharyngeal arch mesenchyme. Impaired Pitx2 function in discrete myocardial regions seems to lead to DORV, AI, and possibly TGA. On the other hand, impaired Pitx2 expression in the CNC leads preferentially to PTA. AAA remodeling is likely to occur owing to impaired cross-talk of the CNC cells with the pharyngeal arch mesenchyme. Thus, Pitx2 appears to be directing left-right identity to the cardiac venous components (e.g., the atria), whereas it appears to be modeling the morphologic arrangement of distinct myocardial components in the arterial pole. These data suggest that altered left-right signaling underlies the etiology of several common congenital cardiac malformations.

Animals↗

PubMed2003

Ventrally emigrating neural tube cells contribute to the normal development of heart and great vessels.

We investigated the contributions of a recently described population of neural tube cells, which participates in the development of a variety of tissues, to the development of the heart and great vessels. These cells, termed as the ventrally emigrating neural tube (VENT) cells, originate in the ventral part of the hindbrain neural tube, emigrate at the site of attachment of the cranial nerves, and populate their respective target tissues. VENT cells of the caudal hindbrain neural tube at the level of the vagus nerve, which were previously reported to migrate into the heart, were tagged with replication-deficient retroviruses containing the LacZ gene in chick embryos, after the emigration of neural crest from this region. In older embryos, VENT cells were detected in a variety of locations including the ventricles, atria, their septa, aorticopulmonary septum, and great vessels of the heart. Immunostaining with a specific marker revealed that VENT cells differentiated into smooth muscle cells of great vessels. Differentiation of VENT cells into cardiac muscle cells was reported previously. Extirpation of the VENT cells prior to their departure from the neural tube resulted in some common cardiovascular malformations: thin-walled ventricles and atria, ventricular and atrial septal defects, persistent truncus arteriosus, and stenosis of the great vessels. These results suggest that a novel population of neural tube cells also contributes to the normal development of the heart and great vessels. Thus, the heart and great vessels develop from three sources of cells: mesoderm, neural crest, and VENT cells.

Animals↗

PubMed2002

Cardiac neural crest ablation alters aortic smooth muscle force and voltage-sensitive Ca2+ responses.

Ablation of the premigratory cardiac neural crest (CNC) from the chick embryo results in a malformed outflow tract vasculature termed persistent truncus arteriosus (PTA). In addition, loss of the CNC disrupts myocardial excitation-contraction (EC) coupling, decreases intracellular Ca2+ transients, and depresses force generation. We examined if similar defects occurred in the neural crest-derived smooth muscle of the aortic arch in a test of the hypothesis that loss of elements from the CNC disrupts EC coupling and force production in the smooth muscle of the tunica media of the aortic arch. Aortic arch segments from chicks (embryonic day 15) displaying PTA generated approximately 43% of stress generated by the aortic arch from sham-operated control embryos during potassium depolarization. The depressed force response was associated with a twofold lower Fura-2 transient. In contrast, force and steady-state Fura-2 signals during endothelin-1 stimulation were unchanged. The differences seen in stress generation with potassium depolarization between sham and PTA displaying embryos were not seen in the descending aorta, a tissue not derived from the neural crest. Protein content and immunostaining revealed no differences in the content of actin, myosin, or dihydropyridine receptor from sham or PTA aortic arch. Our results suggest that the CNC is required for normal aortic arch smooth muscle function and support the hypothesis that the loss of CNC impacts the force generating ability, in part by disruption of the EC-coupling processes and altering Ca(2+)-handling.

Animals↗

PubMed2001

Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator.

The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. Here we show that Cited2-/- embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2-/- embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.

Adrenal Glands↗

PubMed2005

Common arterial trunk associated with a homeodomain mutation of NKX2.6.

Persistent truncus arteriosus (PTA) is a failure of septation of the cardiac outflow tract (OFT) into the pulmonary artery and the aorta. A common arterial trunk (CAT) is often diagnosed as PTA in the absence of evidence of embryological mechanism. We have used autozygosity mapping of a large consanguineous family segregating CAT to map the causative locus to chromosome 8p21. An F151L mutation was identified in the homeodomain of NKX2.6, a transcription factor expressed in murine pharyngeal endoderm and embryonic OFT myocardium. Although expression of Nkx2.6 during murine embryogenesis is strongly suggestive of a role for this gene in heart development, mice homozygous for a targeted mutation of Nkx2.6 are normal. However, in these mice, it has been shown that Nkx2.5 expression expands into regions lacking Nkx2.6, suggesting functional complementation. As transcriptional targets of NKX2.6 are unknown, we investigated functional effects of the mutation in transcriptional and protein interaction assays using NKX2.5 as a surrogate. Introduction of F157L into human NKX2.5 substantially reduced its transcription activating function, its synergism with partners at the atrial natriuretic factor (ANF) and connexin-40 (Cx40) promoters and its specific DNA binding. We tested NKX2.5 target promoters for NKX2.6 activity. NKX2.6 was inactive at ANF but weakly activated transcription of a Cx40 promoter, whereas the F151L mutant lacked this activity. These findings indicate a previously unsuspected role for NKX2.6 in heart development, which should be re-evaluated in more sophisticated model systems.

Amino Acid Sequence↗

PubMed2005

Association of the C677T methylenetetrahydrofolate reductase mutation with congenital heart diseases.

BACKGROUND: To investigate whether the cytosine-to-thymine mutation at base 677 of the gene for methylenetetrahydrofolate reductase (MTHFR) is associated with congenital heart diseases (CHD), using high throughput heteroduplex analysis based upon the powerful technique of denaturing high-performance liquid chromatography. METHODS: We investigated the MTHFR genotype of a cytosine-to-thymine mutation at base 677 for 213 patients of CHDs as confirmed by cardiac catheterization and also for 195 healthy controls. RESULTS: The overall genotype frequencies of the MTHFR C677T polymorphism were not significantly different between the CHD patients and the healthy control (P = 0.345). Furthermore, taking various subgroups of CHD patients into consideration, we noted a significantly increased proportion of homozygous TT genotypes for patients suffering from valvular pulmonary stenosis (PS) or pulmonary atresia with an intact ventricular septum (PA + IVS) (p = 0.0005). For patients revealing heterotaxy syndrome, a conotruncal anomaly including tetralogy of Fallot, an interruption of the aortic arch, persistent truncus arteriosus, and aortopulmonary window, no statistically significant difference existed. CONCLUSIONS: The discrepancy in the distribution of MTHFR genotypes amongst various subtypes of CHD reflects some heterogeneity in the developmental mechanism of CHD. The increased percentage of homozygous TT genotypes might contribute to the pathogenesis of valvular PS and PA + IVS.

Asian People↗

PubMed2006

Rescue of morphogenetic defects and of retinoic acid signaling in retinaldehyde dehydrogenase 2 (Raldh2) mouse mutants by chimerism with wild-type cells.

Retinoic acid (RA), the active vitamin A derivative, is an important developmental signaling molecule in vertebrates. In this study, we have assessed whether minimal numbers and/or specific distributions of RA-producing cells can support normal mouse embryonic development. Retinaldehyde dehydrogenase 2 (RALDH2) is the main RA-synthesizing enzyme acting during development. We have generated an embryonic stem (ES) cell line homozygous for an Raldh2 gene disruption, and have analyzed chimeric embryos with various contributions of wild-type cells. Whereas embryos almost completely derived from Raldh2(-/-) cells phenocopy the corresponding germline null mutants, the presence of even small numbers (<10%) of wild-type cells can rescue most of the morphogenetic defects, including embryonic turning and axial elongation, and left-right looping of the heart tube. No consistent bias in the distribution of wild-type cells was observed in the phenotypically rescued Raldh2(-/-) chimeras. Analysis of an RA-sensitive transgene indicates that RA can diffuse from wild-type cells and elicit a widespread transcriptional response in Raldh2-deficient cells. Our results show that few wild-type RA-producing cells, even when present in apparent random distributions, can support early morphogenesis of the mouse embryo. However, the Raldh2(-/-) chimeric fetuses display lung abnormalities, persistent truncus arteriosus, and abnormal myocardial differentiation, showing that subsequent RA-dependent events cannot be fully rescued by the mosaic presence of wild-type cells.

Abnormalities, Multiple↗