Chiral blastomere arrangement dictates zygotic left-right asymmetry pathway in snails.

Most animals display internal and/or external left-right asymmetry. Several mechanisms for left-right asymmetry determination have been proposed for vertebrates and invertebrates but they are still not well characterized, particularly at the early developmental stage. The gastropods Lymnaea stagnalis and the closely related Lymnaea peregra have both the sinistral (recessive) and the dextral (dominant) snails within a species and the chirality is hereditary, determined by a single locus that functions maternally. Intriguingly, the handedness-determining gene(s) and the mechanisms are not yet identified. Here we show that in L. stagnalis, the chiral blastomere arrangement at the eight-cell stage (but not the two- or four-cell stage) determines the left-right asymmetry throughout the developmental programme, and acts upstream of the Nodal signalling pathway. Thus, we could demonstrate that mechanical micromanipulation of the third cleavage chirality (from the four- to the eight-cell stage) leads to reversal of embryonic handedness. These manipulated embryos grew to 'dextralized' sinistral and 'sinistralized' dextral snails-that is, normal healthy fertile organisms with all the usual left-right asymmetries reversed to that encoded by the mothers' genetic information. Moreover, manipulation reversed the embryonic nodal expression patterns. Using backcrossed F(7) congenic animals, we could demonstrate a strong genetic linkage between the handedness-determining gene(s) and the chiral cytoskeletal dynamics at the third cleavage that promotes the dominant-type blastomere arrangement. These results establish the crucial importance of the maternally determined blastomere arrangement at the eight-cell stage in dictating zygotic signalling pathways in the organismal chiromorphogenesis. Similar chiral blastomere configuration mechanisms may also operate upstream of the Nodal pathway in left-right patterning of deuterostomes/vertebrates.

Hairy cell leukemia in a patient with situs inversus totalis: an extremely rare combination.

Hairy cell leukemia is a rare cancer of the blood. The occurrence of hairy cell leukemia with another very rare genetic disorder makes us question whether it is just a coincidence. This article reports the first case of hairy cell leukemia in a patient with situs inversus totalis in western literature. There have been studies into the pathogenesis of situs inversus totalis that suggest it is caused by the failure of embryonic cells to properly rotate during embryogenesis. On the molecular level, the nodal cilia, which are responsible for embryonic rotation, are built by transport through the KIF3 complex - a kinesin superfamily of molecular motors. The KIF3 complex is also responsible for N-cadherin movement in cells. Furthermore, it is well known that these cell adhesion molecules play an important role in carcinogenesis and its progression. This report attempts to link the rare conditions and propose a possible genetic relationship between the two.

Regulation of left-right patterning in mice by growth/differentiation factor-1.

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of structurally related polypeptides that are capable of regulating cell growth and differentiation in a wide range of embryonic and adult tissues. Growth/differentiation factor-1 (Gdf-1, encoded by Gdf1) is a TGF-beta family member of unknown function that was originally isolated from an early mouse embryo cDNA library and is expressed specifically in the nervous systemin late-stage embryos and adult mice. Here we show that at early stages of mouse development, Gdfl is expressed initially throughout the embryo proper and then most prominently in the primitive node, ventral neural tube, and intermediate and lateral plate mesoderm. To examine its biological function, we generated a mouse line carrying a targeted mutation in Gdf1. Gdf1-/- mice exhibited a spectrum of defects related to left-right axis formation, including visceral situs inversus, right pulmonary isomerism and a range of cardiac anomalies. In most Gdf1-/- embryos, the expression of Ebaf (formerly lefty-1) in the left side of the floor plate and Leftb (formerly lefty-2), nodal and Pitx2 in the left lateral plate mesoderm was absent, suggesting that Gdf1 acts upstream of these genes either directly or indirectly to activate their expression. Our findings suggest that Gdf1 acts early in the pathway of gene activation that leads to the establishment of left-right asymmetry.

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.

Type ID unconventional myosin controls left-right asymmetry in Drosophila.

Breaking left-right symmetry in Bilateria embryos is a major event in body plan organization that leads to polarized adult morphology, directional organ looping, and heart and brain function. However, the molecular nature of the determinant(s) responsible for the invariant orientation of the left-right axis (situs choice) remains largely unknown. Mutations producing a complete reversal of left-right asymmetry (situs inversus) are instrumental for identifying mechanisms controlling handedness, yet only one such mutation has been found in mice (inversin) and snails. Here we identify the conserved type ID unconventional myosin 31DF gene (Myo31DF) as a unique situs inversus locus in Drosophila. Myo31DF mutations reverse the dextral looping of genitalia, a prominent left-right marker in adult flies. Genetic mosaic analysis pinpoints the A8 segment of the genital disc as a left-right organizer and reveals an anterior-posterior compartmentalization of Myo31DF function that directs dextral development and represses a sinistral default state. As expected of a determinant, Myo31DF has a trigger-like function and is expressed symmetrically in the organizer, and its symmetrical overexpression does not impair left-right asymmetry. Thus Myo31DF is a dextral gene with actin-based motor activity controlling situs choice. Like mouse inversin, Myo31DF interacts and colocalizes with beta-catenin, suggesting that situs inversus genes can direct left-right development through the adherens junction.

[A rare cause of left lower quadrant abdominal pain: acute appendicitis with situs inversus totalis]. / Karin sol alt kadran agrisinin nadir bir sebebi: Situs inversus totalisli hastada akut apandisit.

For the patient admitted with right lower quadrant abdominal pain, acute appendicitis is the most frequently considered diagnosis. Appendectomy is the most common of all emergency operations. However, there may be several reasons for left lower quadrant abdominal pain. Situs inversus totalis is an anomaly that occurs during embryonic development when intraabdominal and intrathoracic organs have reverse localization. In this case report, we present a patient who was admitted with left lower quadrant abdominal pain and was diagnosed as situs inversus totalis and acute appendicitis. In view of the legal repercussions for doctors as a result of erroneous diagnosis and treatment, we think that adequate evaluation of the studies in the emergency service is important and that the radiological investigations have to be used appropriately and sufficiently.

Ectodermal syndecan-2 mediates left-right axis formation in migrating mesoderm as a cell-nonautonomous Vg1 cofactor.

Heparan sulfate proteoglycans expressed on the Xenopus animal cap ectoderm have been implicated in transmitting left-right information to heart and gut primordia. We report here that syndecan-2 functions in the ectoderm to mediate cardiac and visceral situs, upstream of known asymmetrically expressed genes but independently of its ability to mediate fibronectin fibrillogenesis. Left-right development is dependent on a distinct subset of glycosaminoglycan attachment sites on syndecan-2. A novel in vivo approach with enterokinase demonstrates that syndecan-2 functions in left-right patterning during early gastrulation. We describe a cell-nonautonomous role for ectodermal syndecan-2 in transmitting left-right information to migrating mesoderm. The results further suggest that this function may be related to the transduction of Vg1-related signals.

A human syndrome caused by immotile cilia.

Four subjects who produced immotile sperm were studied. In three of the subjects, who had frequent bronchitis and sinusitis, there was no mucociliary transport, as measured by tracheobronchial clearance. Electron microscopy indicated that cilia from cells of these patients lack dynein arms.

An interrupted inferior vena cava in a situs inversus. Case report and review of the literature.

Situs inversus with interrupted inferior vena cava is an uncommon anatomic variant found in the abdominal and thoracic viscera. In this report, we present a 59-year-old woman with this variation, found during gross anatomical dissection. While this type of variation has been variable, in the present case the hepatic veins drained directly into a very short (2.2 cm) inferior vena cava. The infrarenal component of the inferior vena cava was present and drained into the azygos and hemiazygos veins. Clinical considerations of this variant anatomy are of interest, as they may present in patients as pathology on cross sectional imaging.

Caudal dysgenesis, sirenomelia, and situs inversus totalis: a primitive defect in blastogenesis.

Caudal dysgenesis (CD) constitutes a heterogeneous spectrum of congenital caudal anomalies, including varying degrees of agenesis of the vertebral column, as well as anorectal and genitourinary anomalies. Sirenomelia, characterized by a fusion of the lower limbs, could represent the most severe end of this spectrum. The two main debated pathogenic hypotheses are an aberrant vascular supply versus a primary axial mesoderm defect. We present the autopsy findings of two fetuses of non-diabetic mothers, with normal karyotype. Both fetuses presented situs inversus associated with a CD, in one case consisting of sirenomelia, establishing a very rare association profile that might be random. This association also suggests the occurrence of a common pathogenic mechanism, in accordance to recent genetic data, such as displayed in the Kif3A murine mutation phenotype. Some cases of sirenomelia and CD could represent developmental field defects of blastogenesis involving the caudal mesoderm, rather than being related to vascular insufficiency.

What Determines Whether the Great Arteries Are Normally or Abnormally Related?

The situs, or pattern of anatomic organization, of the subarterial infundibulum and of the great arteries and the degree of development of the subarterial infundibulum largely determine whether the great arteries are normally or abnormally related. There are 2 types of situs: solitus (normal) and inversus (a mirror image of solitus). Situs ambiguus means that the pattern of anatomic organization is uncertain or unknown. Infundibular development varies from absent, to atretic, to severely stenotic, to mildly or moderately stenotic; great arteries are solitus normally related or inversus normally related, respectively. When the situs of the subarterial infundibulum and the situs of the great arteries are discordant (different), then the great arteries are abnormally related. Equations indicating the situs of the infundibulum and the situs of the great arteries show whether infundibuloarterial (IA) situs concordance or discordance is present. Many types of IA anomalies typically have IA situs discordance, including transposition of the great arteries, double-outlet right ventricle, double-outlet left ventricle, and anatomically corrected malposition of the great arteries. However, tetralogy of Fallot and truncus arteriosus typically have IA situs concordance, with hypoplasia or atresia of the subpulmonary infundibulum. The relation between the great arteries in tetralogy of Fallot and in truncus arteriosus is almost normal. The IA equations demonstrate the infundibular situs, the great arterial situs, the IA situs concordance or discordance, and the degree of development of the infundibulum. The infundibular situs and the great arterial situs are the formulas or "recipes" for each of the abnormal types of conotruncal malformation.

Left-right lineage analysis of AV cushion tissue in normal and laterality defective Xenopus hearts.

The majority of complex congenital heart defects occur in individuals who are afflicted by laterality disease. We hypothesize that the prevalence of valvuloseptal defects in this population is due to defective left-right patterning of the embryonic atrioventricular (AV) canal cushions, which are the progenitor tissue for valve and septal structures in the mature heart. Using embryos of the frog Xenopus laevis, this hypothesis was tested by performing left-right lineage analysis of myocytes and cushion mesenchyme cells of the superior and inferior cushion regions of the AV canal. Lineage analyses were conducted in both wild-type and laterality mutant embryos experimentally induced by misexpression of ALK4, a type I TGF-beta receptor previously shown to modulate left-right axis determination in Xenopus. We find that abnormalities in overall amount and left-right cell lineage composition are present in a majority of ALK4-induced laterality mutant embryos and that much variation in the nature of these abnormalities exists in embryos that exhibit the same overall body situs. We propose that these two parameters of cushion tissue formation-amount and left-right lineage origin-are important for normal processes of valvuloseptal morphogenesis and that defective allocation of cells in the AV canal might be causatively linked to the high incidence of valvuloseptal defects associated with laterality disease.

Left-right determination.

Recent advances have given us new insights into the molecular basis of organ position. A gene cascade that determines left-right positioning of organ primordia has emerged. In here we present the current knowledge of the molecular determinants of organ positioning during vertebrate embryogenesis.

Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies.

Asplenia syndrome is characterized by complex congenital heart defects, asplenia and abdominal heterotaxy. Recent interest in the syndrome has been increased by new knowledge arising from animal models and by continuing improvements in surgical outcome in childhood. To further elucidate the embryologic timing and mechanisms of the asplenia syndrome, 32 necropsy cases were reviewed and 487 published autopsy cases were reanalyzed at the hospital. The most common congenital heart defects were atrial septal defects, common atrioventricular canals and conotruncal anomalies. With use of current information on the timing of normal development, it was hypothesized that most defects originate at Streeter Horizon XIII; patients averaged 3.2 Horizon XIII defects, more than at any other stage. Distribution was unimodal. Extracardiac anomalies also exhibited a developmental spectrum. Because the normal spleen develops by Horizon XIII, asplenia, the sine qua non of the syndrome, originates then or earlier. Abnormal pulmonary lobation occurred in 80% of cases, with right isomerism occurring most often; pulmonary branching asymmetry also originates at or before Horizon XIII. Abdominal heterotaxy occurred in 72% of cases, but the timing of origin is unclear. Anomalies of other systems, including genitourinary, musculoskeletal, endocrine, and nervous systems, develop later (typically XV to XXIII); specific anomalies were less frequent, although much more prevalent than in the general population. It is concluded that asplenia syndrome is a focal developmental disturbance in laterality which occurs primarily at Horizon XIII.

Left-right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease.

Proper morphogenesis and positioning of internal organs requires delivery and interpretation of precise signals along the anterior-posterior, dorsal-ventral, and left-right axes. An elegant signaling cascade determines left- versus right-sided identity in visceral organs in a concordant fashion, resulting in a predictable left-right (LR) organ asymmetry in all vertebrates. The complex morphogenesis of the heart and its connections to the vasculature are particularly dependent upon coordinated LR signaling pathways. Disorganization of LR signals can result in myriad congenital heart defects that are a consequence of abnormal looping and remodeling of the primitive heart tube into a multi-chambered organ. A framework for understanding how LR asymmetric signals contribute to normal organogenesis has emerged and begins to explain the basis of many human diseases of LR asymmetry. Here we review the impact of LR signaling pathways on cardiac development and congenital heart disease.

Echocardiographic considerations in demonstrating complex anatomy of criss-cross atrioventricular valves and discordant atrioventricular and ventriculoarterial relations.

The associated features of 1-looping of the ventricles (ventricular inversion) with D-transposition of the great vessels and criss-crossing atrioventricular valves are an unusual constellation of cardiac anomalies resulting in corrected transposition physiology. The following case presentation depicts the fetal and postnatal considerations of two-dimensional and color Doppler echocardiography in accurately detailing the complex intracardiac connections associated with this arrangement and also warns of the potential pitfalls in echocardiographic assessment.

Does an equivalent of the "ventral node" exist in chick embryos? A scanning electron microscopic study.

The internal organs of vertebrates show species-specific left-right (L-R) asymmetries. Questions on the embryonic origin of these asymmetries have been fascinating embryologists since the 19th century. During the past years, remarkable progress has been made in answering these questions. Evolutionary highly conserved molecular signaling cascades have been identified that start from Hensen's node and transfer side-specific identity to the embryonic left and right halves. However, the question of what initiates these signaling cascades has remained unanswered. Studies on mouse embryos have shown that the ventral surface of Hensen's node consists of a ciliated epithelium called the ventral node. Recent findings suggest that the monocilia of ventral nodel cells generate a leftward flow of extracellular fluid possibly leading to the accumulation of an unknown morphogen at the left of the node, which then might start the signaling cascades. This hypothesis might explain the fact that gene defects causing ciliary dyskinesia are frequently associated with situs anomalies. Studies on chick embryos led to the discovery of the L-R signaling cascades. However, whether an equivalent of the ventral node exists in avian embryos remained unknown. Therefore, I examined the endoderm and epiblast of early chick embryos for the presence of monociliated cells. In the endoderm, a population of monociliated cells indeed was present. These cells, however, were neither confined to the area of Hensen's node nor did they form the predominant cell population at this location. In the epiblast, monociliated cells formed the predominant cell population at the periphery of the blastodisc but only a relatively small subpopulation of epiblast cells at Hensen's node. These findings suggest that, in the early chick embryo, an equivalent of the ventral node of mouse embryos neither exists on the ventral nor the dorsal surface of Hensen's node. It is unlikely that nodal cilia are required for initiating the L-R patterning in chick embryos.

Combination of annular pancreas and partial situs inversus: a multiple organ malrotation syndrome associated with duodenal obstruction.

A combination of annular pancreas and partial situs inversus has been encountered in three babies who presented as duodenal obstruction. All the abnormalities can be explained on the basis of multiple organ malrotation involving the duodenum, pancreas, liver, stomach, and indirectly, the spleen; hence, the term multiple organ malrotation syndrome (MOMS). The heart maintains its normal left side location in this condition. Similarly the remaining small bowel, large bowel, and appendix are normally located. It is proposed that the triad of intestinal obstruction as suggested by vomiting and visible peristalsis, left-sided liver in the presence of laevocardia, and radiographic appearance of reversed double bubble, be considered as indicating MOMS.

Jejunoileal atresia and associated malformations: correlation with the timing of in utero insult.

PURPOSE: Duodenal atresia is associated with a higher incidence of associated congenital malformations than jejunoileal atresia, supporting the hypothesis that the duodenal obstruction occurs early in fetal life. In this study, the authors analyzed the incidence of major associated malformations in jejunal atresia (JA) and ileal atresia (IA) to determine if there is a positive correlation between the proximity of the intestinal atresia and the association of other major anomalies. METHODS: Records of all patients with jejunoileal atresias treated at the authors' institution between 1980 and 1997 were examined. RESULTS: There were 83 patients with jejunoileal atresias, 38 with JA, and 45 with IA. Sixteen (42%) of the JA patients had an associated major congenital malformation, whereas only 1 (2%) of the IA patients had an associated malformation. A single atresia was found in 18 (47%) of JA patients and 41 (91%) of IA patients. Twenty (53%) of the JA patients had either multiple or apple-peel atresia. Thirteen patients (16%) died, 11 with JA, and 2 with IA. Of the 11 patients with JA who died, 6 had multiple atresias, 4 had cystic fibrosis, and 1 had small bowel volvulus. CONCLUSION: The higher incidence of associated major congenital extraintestinal malformations in JA compared with IA patients suggests that some cases of JA may arise from a malformative process.

[Cerebral abscess disclosing tetralogy of Fallot with situs inversus in adulthood]. / Abcès cérébral révélant à l'âge adulte une tétralogie de Fallot sur situs inversus.

The authors report the case of tetralogy of Fallot (TOF) associated with situs inversus, the first description of this rare association in a previously asymptomatic adult. A 32 years old chauffeur was admitted to hospital with pyrexia and convulsions due to a left temporo-parietal cerebral abscess which had a favourable outcome. The chest X-ray and Doppler echocardiographic study showed a TOF with a high infundibular stenosis and dextrocardia. Abdominal ultrasonography confirmed a complete situs inversus. The good tolerance was attributed to the equilibrated character of the TOF. The orientation of the heart and the cono-truncal septation occur at different times during embryogenesis. However, there are genetic arguments in favour of the non-fortuitous nature of this association.