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PubMed1988

Embryogenesis of ureteral anomalies: a unifying theory.

Extensive gross, microscopic and clinical studies of various ureteral anomalies have enabled investigators to set forth theories regarding the aetiologies of these anomalies consistent with observed fact. Synthesis of these observations allows for a simplified classification of mega-ureter (primary obstructed, reflux and non-obstructed, non-reflux mega-ureters), ureterocele, duplex ureters and ectopic ureters based upon some combination of mesenchymal differentiation anomalies and location anomalies. A defect early in mesenchymal differentiation would be expected to result in panureteral disease. A defect later in development would result in a focal abnormality anywhere along the course of the ureter. Influence upon ureteral bud mesenchyme by local expansion factors in the bladder base may result in various types of ureterocele. Position of the ureteral orifice on the trigone or in Wolffian duct derivatives would occur in accordance with the Weigert-Meyer principle and would correlate with upper tract dysplasias. Thus, an attempt has been made to systematize and trace the origins of mega-ureter, ureterocele, duplex ureters and ectopic ureters to defects of differentiation of the basic mesoblastic cell in aberrant locations of the ureteral bud.

Cell Differentiation↗
PubMed2006

Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs.

Pitx2 is expressed in developing visceral organs on the left side and is implicated in left-right (LR) asymmetric organogenesis. The asymmetric expression of Pitx2 is controlled by an intronic enhancer (ASE) that contains multiple Foxh1-binding sites and an Nkx2-binding site. These binding sites are essential and sufficient for asymmetric enhancer activity and are evolutionarily conserved among vertebrates. We now show that mice that lack the ASE of Pitx2 (Pitx2(Delta)(ASE/)(Delta)(ASE) mice) fail to manifest left-sided Pitx2 expression and exhibit laterality defects in most visceral organs, although the position of the stomach and heart looping remain unaffected. Asymmetric Pitx2 expression in some domains, such as the common cardinal vein, was found to be induced by Nodal signaling but to be independent of the ASE of Pitx2. Expression of Pitx2 appears to be repressed in a large portion of the heart ventricle and atrioventricular canal of wild-type mice by a negative feedback mechanism at a time when the gene is still expressed in its other domains. Rescue of the early phase of asymmetric Pitx2 expression in the left lateral plate of Pitx2(Delta)(ASE/)(Delta)(ASE) embryos was not sufficient to restore normal organogenesis, suggesting that continuous expression of Pitx2 in the lineage of the left lateral plate is required for situs-specific organogenesis.

Animals↗
PubMed1998

Molecular mechanisms of vertebrate left-right development.

Patterning of all tissues and organs in the vertebrate embryo occurs along the dorsoventral (DV), anteroposterior (AP), and left-right (LR) body axes. Whereas significant progress has been made in identifying the processes underlying DV and AP patterning, relatively little is known about mechanisms guiding LR development. The significant incidence of human disease conditions associated with LR laterality defects, particularly those of the cardiovascular system, underscores the importance of understanding how LR asymmetries become established in the embryo. The focus of this review is on recently identified genes that are involved in generation of vertebrate LR asymmetry, and the proposed cellular and molecular mechanisms by which they might function in initiation, propagation and interpretation of LR patterning information.

Animals↗
PubMed2003

Fibrinogens Kosai and Ogasa: Bbeta15Gly-->Cys (GGT-->TGT) substitution associated with impairment of fibrinopeptide B release and lateral aggregation.

We found two heterozygous dysfibrinogenemias, designated fibrinogen Kosai and fibrinogen Ogasa. Kosai was associated with arteriosclerosis obliterans but Ogasa showed no bleeding or thrombotic tendencies. The plasma fibrinogen concentrations from the two propositi (Ogasa and Kosai) were much lower when determined by the thrombin-time method (0.94 and 1.06 g L(-1), respectively) than when determined by the immunological method (2.87 and 2.72 g L(-1), respectively). We performed DNA sequencing and functional analyses to clarify the relationship between the structural and functional abnormalities. Genetic analysis of PCR-amplified DNA from the propositi identified the heterozygous substitution Bbeta15Gly-->Cys (GGT-->TGT). Western blotting analysis of purified fibrinogen revealed the existence of albumin-fibrinogen complexes. Functional analyses indicated that compared with the normal control, the propositi's fibrinogen released only half the normal amount of fibrinopeptide B and showed markedly impaired polymerization. In addition, the observation of thinner fibers in fibrin clots (by scanning electron microscopy) indicated markedly defective lateral aggregation in the variant fibrinogens. The impaired functions may be due to the substitution of Cys for Bbetao15Gly plus the existence of some additional disulfide-bonded forms.

Adult↗
PubMed2003

Na,K-ATPase is essential for embryonic heart development in the zebrafish.

Na,K-ATPase is an essential gene maintaining electrochemical gradients across the plasma membrane. Although previous studies have intensively focused on the role of Na,K-ATPase in regulating cardiac function in the adults, little is known about the requirement for Na,K-ATPase during embryonic heart development. Here, we report the identification of a zebrafish mutant, heart and mind, which exhibits multiple cardiac defects, including the primitive heart tube extension abnormality, aberrant cardiomyocyte differentiation, and reduced heart rate and contractility. Molecular cloning reveals that the heart and mind lesion resides in the alpha1B1 isoform of Na,K-ATPase. Blocking Na,K-ATPase alpha1B1 activity by pharmacological means or by morpholino antisense oligonucleotides phenocopies the patterning and functional defects of heart and mind mutant hearts, suggesting crucial roles for Na,K-ATPase alpha1B1 in embryonic zebrafish hearts. In addition to alpha1B1, the Na,K-ATPase alpha2 isoform is required for embryonic cardiac patterning. Although the alpha1B1 and alpha2 isoforms share high degrees of similarities in their coding sequences, they have distinct roles in patterning zebrafish hearts. The phenotypes of heart and mind mutants can be rescued by supplementing alpha1B1, but not alpha2, mRNA to the mutant embryos, demonstrating that alpha1B1 and alpha2 are not functionally equivalent. Furthermore, instead of interfering with primitive heart tube formation or cardiac chamber differentiation, blocking the translation of Na,K-ATPase alpha2 isoform leads to cardiac laterality defects.

Animals↗
PubMed1997

Rap1 overexpression reveals that activated RasD induces separable defects during Dictyostelium development.

One of the Dictyostelium ras genes, rasD, is expressed preferentially in prestalk cells at the slug stage of development and overexpression of this gene containing a G12T activating mutation causes the formation of aberrant multitipped aggregates that are blocked from further development (Reymond et al., 1986, Nature, 323, 340-343). The ability of the Dictyostelium rap1 gene to suppress this abnormal developmental phenotype was investigated. The rap1 gene and G12V activated and G10V negative mutant forms of the rap1 gene were independently linked to the rasD promoter and each construct used to transform M1, a Dictyostelium cell line expressing RasD[G12T]. Transformants of M1 that expressed Rap1 or Rap1[G12V] protein still formed multitipped aggregates, but most tips were able to complete development and form fruiting bodies. Cell lines showing this modified phenotype were designated ME (multitipped escape). The rap1[G10V] construct did not modify the M1 phenotype. These data suggest that overexpression of RasD[G12T] has two effects, the formation of a multitipped aggregate and a block in subsequent differentiation and that the expression of Rap1 or Rap1[G12V] reverses only the latter. Differentiation of ME cells in low density monolayers showed the identical low level of stalk and spore cell formation seen for M1 cells under the same conditions. Thus the cell autonomous defect in monolayer differentiation induced in the M1 strain was not corrected in the ME strain. Cell type-specific gene expression during the development of M1 cells is dramatically altered: prestalk cell-specific gene expression is greatly enhanced, whereas prespore-specific gene expression is almost suppressed (Louis et al., 1997, Mol. Biol. Cell, 8, 303-312). During the development of ME cells, ecmA mRNA levels were restored to those seen for Ax3, and tagB mRNA levels were also markedly reduced, although not to Ax3 levels. cotC expression in ME cells was enhanced severalfold relative to M1, although levels were still lower than those observed during the development of Ax3. The low expression of car1 mRNA during early development of the M1 strain remained low during the development of ME cells. These data are consistent with the idea that the expression of RasD[G12T] affects two independent and temporally separated events and that only the later defect is reversed by rap1.

Animals↗
PubMed1997

Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia, and multicystic dysplastic kidneys: expanding the phenotype of Cumming syndrome.

We report on a fetus with tetramelic campomelia, polysplenia, multicystic dysplastic kidneys, and cervical lymphocele. This condition is similar to the autosomal recessive condition described by Cumming et al. [1986: Am J Med Genet 25:783-790] and is different from campomelic syndrome. In addition, our case had anomalies not previously described in this condition, including abnormal lung lobation with bilateral left bronchial morphology, dextrocardia, total anomalous pulmonary venous return, a left superior vena cava, and a right aortic arch. The pancreas was short, with absence of the body and tail. These anomalies are similar to those found in the polyasplenia spectrum. We suggest that the syndrome reported by Cumming et al. may be expanded to include polysplenia with heterotaxia and that Cumming syndrome may be considered another autosomal recessive condition associated with a laterality defect.

Abnormalities, Multiple↗
PubMed1998

Anencephaly-associated aganglionosis.

Autopsies of 12 consecutively born infants with anencephaly showed varying degrees of aganglionosis and lateralization defects in four of them. This seemingly regular occurrence of these three defects together suggests that they are caused by an aberration of blastogenesis that results in a polytopic field defect.

Anencephaly↗
PubMed2000

Primary ciliary dyskinesia (PCD).

This article summarizes the current state of the scientific and clinical knowledge that relates to primary ciliary dyskinesia (PCD). Although PCD is a rare disease with a prevalence of 1 in 20,000 it has a well recognized morbidity. It is believed that an accurate diagnosis and the application of appropriate management can significantly reduce this morbidity. The cilia themselves are highly complicated organelles that perform important functions, particularly in the respiratory and reproductive tracts, and they have been the focus of many years of research. Our current knowledge of ciliary function and mucociliary clearance is summarized, and the relationship with laterality defects is discussed. A phenotype resembling PCD is also seen in animal models, and some of these are described before reviewing the clinical aspects of PCD in humans and new developments in the field that may have implications for the future investigation and management of affected individuals.

Animals↗
PubMed2005

Trisomy 8 mosaicism in a patient with heterotaxia.

Constitutional trisomy 8 mosaicism (CT8M) is a relatively rare trisomy in humans with a characteristic phenotype. We report an infant with the characteristic CT8M phenotype in addition to heterotaxia. A number of chromosomal abnormalities have been reported in association with laterality defects but this is the first time heterotaxia is reported in CT8M. In addition to expanding CT8M phenotype, our report may provide insight into the mechanism of heterotaxia.

Chromosomes, Human, Pair 8↗
PubMed2007

Development and function of the mammalian spleen.

The vertebrate spleen has important functions in immunity and haematopoiesis, many of which have been well studied. In contrast, we know much less about the mechanisms governing its early embryonic development. However, as a result of work over the past decade-mostly using knockout mice--significant progress has been made in unravelling the genetic processes governing the spleen's early development. Key genetic regulators, such as Tlx1 and Pbx1, have been identified, and we know some of the early transcriptional hierarchies that control the early patterning and proliferation of the splenic primordium. In mouse and humans, asplenia can arise as a result of laterality defects, or the spleen can be absent with no other discernible abnormalities. Surprisingly, given the spleen's diverse functions, asplenic individuals suffer no major haematopoietic or immune defects apart from a susceptibility to infection with encapsulated bacteria. Recent evidence has shed light on a previously unknown role of the spleen in the development and maintenance of specific B cell populations that are involved in the initial response to infection caused by encapsulated bacteria. The lack of these populations in asplenic mice and humans may go some way to explaining this susceptibility.

Animals↗
PubMed2001

MLC3F transgene expression in iv mutant mice reveals the importance of left-right signalling pathways for the acquisition of left and right atrial but not ventricular compartment identity.

Abstract Transcriptional differences between left and right cardiac chambers are revealed by an nlacZ reporter transgene controlled by regulatory sequences of the MLC3F gene, which is expressed in the left ventricle (LV), atrioventricular canal (AVC), and right atrium (RA). To examine the role of left-right signalling in the acquisition of left and right chamber identity, we have investigated MLC3F transgene expression in iv mutant mice. iv/iv mice exhibit randomised direction of heart looping and an elevated frequency of associated laterality defects, including atrial isomerism. At fetal stages, 3F-nlacZ-2E transgene expression remains confined to the morphological LV, AVC, and RA in L-loop hearts, although these appear on the opposite side of the body. In cases of morphologically distinguishable right atrial appendage isomerism, both atrial appendages show strong transgene expression. Conversely, specimens with morphological left atrial appendage isomerism show only weak expression in both atrial appendages. The earliest left-right atrial differences in the expression of the 3F-nlacZ-2E transgene are observed at E8.5. DiI labelling experiments confirmed that transcriptional regionalisation of the 3F-nlacZ-2E transgene at this stage reflects future atrial chamber identity. In some iv/iv embryos at E8.5, the asymmetry of 3F-nlacZ-2E expression was lost, suggesting atrial isomerism at the transcriptional level prior to chamber formation. These data suggest that molecular specification of left and right atrial but not ventricular chambers is dependent on left-right axial cues.

Animals↗
PubMed1980

Teratogenic potential of cocaine hydrochloride in CF-1 mice.

This investigation revealed that cocaine hydrochloride was teratogenic when administered in nontoxic doses to gravid CF-1 mice on Days 7-12 of gestation. The teratogenic susceptibility of the CF-1 mouse fetus to cocaine hydrochloride was evident throughout this portion of the gestation period. The early appearance of eye defects and the occurrence of skeletal defects later in gestation after cocaine hydrochloride challenge paralleled the sequence of ontogenesis.

Abnormalities, Drug-Induced↗
PubMed2006

The murine Dnali1 gene encodes a flagellar protein that interacts with the cytoplasmic dynein heavy chain 1.

Axonemal dyneins are large motor protein complexes generating the force for the movement of eukaryotic cilia and flagella. Disruption of axonemal dynein function leads to loss of ciliary motility and can result in male infertility or lateralization defects. Here, we report the molecular analysis of a murine gene encoding the dynein axonemal light intermediate chain Dnali1. The Dnali1 gene is localized on chromosome 4 and consists of six exons. It is predominantly expressed within the testis but at a lower level Dnali1 transcripts were also observed in different murine tissues, which exhibit cilia. Two transcript variants were detected, generated by the usage of two alternative polyadenylation signals within exon 6. Antibodies were raised against a GST-Dnali1 fusion protein and used to localize Dnali1 within differentiating male germ cells. Dnali1 is strongly expressed in spermatids but was also detected in spermatocytes. Moreover, the Dnali1 protein was localized in cilia of the trachea as well as in flagella of mature sperm supporting its function as an axonemal dynein. To identify putative Dnali1 interacting polypeptides, a yeast two-hybrid approach was performed using a murine testicular cDNA library. By this assay, the C-terminal part of the cytoplasmic dynein heavy chain 1 was identified as a putative interacting polypeptide of Dnali1. The interaction between the axonemal and the cytoplasmic dynein fragments was proven by co-immuno and co-localization experiments.

Amino Acid Sequence↗
PubMed1998

Gap junctions are involved in the early generation of left-right asymmetry.

Invariant left-right asymmetry of the visceral organs is a fundamental feature of vertebrate embryogenesis. While a cascade of asymmetrically expressed genes has been described, the embryonic mechanism that orients the left-right axis relative to the dorsoventral and anteroposterior axes (a prerequisite for asymmetric gene expression) is unknown. We propose that this process involves dorsoventral differences in cell-cell communication through gap junctions composed of connexin proteins. Global modulation of gap junctional states in Xenopus embryos by pharmacological agents specifically induced heterotaxia involving mirror-image reversals of heart, gut, and gall bladder. Greatest sensitivity was observed between st. 5 and st. 12, well before the onset of organogenesis. Moreover, heterotaxia was also induced following microinjection of dominant negative and wild-type connexin mRNAs to modify the endogenous dorsoventral difference in junctional communication. Heterotaxia was induced by either blocking gap junction communication (GJC) dorsally or by introducing communication ventrally (but not the reverse). Both connexin misexpression and exposure to GJC-modifying drugs altered expression of the normally left-sided gene XNR-1, demonstrating that GJC functions upstream of XNR-1 in the pathway that patterns left-right asymmetry. Finally, lineage analysis to follow the progeny of microinjected cells indicated that they generally do not contribute the asymmetric organs. Together with the early sensitivity window, this suggests that GJC functions as part of a fundamental, early aspect of left-right patterning. In addition, we show that a potential regulatory mutation in Connexin43 is sufficient to cause heterotaxia. Despite uncertainty about the prevalence of the serine364 to proline substitution reported in human patients with laterality defects, the mutant protein is both a mild hypomorph and a potent antimorph as determined by the effect of its expression on left-right patterning. Taken together, our data suggest that endogenous dorsoventral differences in GJC within the early embryo are needed to consistently orient left-right asymmetry.

Animals↗
PubMed1992

A detailed linkage map of subtelomeric murine chromosome 12 region including the situs inversus mutation locus IV.

A mouse model is an invaluable tool to tackle genesis of human congenital diseases that have so far eluded human studies. Homozygote for the i.v. mutation, the murine Si/Col strain presents a left-right lateralization defect of thoracic and abdominal organs and heart defects very similar to human ones. This i.v. mutation has been mapped to the region between the Aat and Igh-C loci, suggesting the presence of an equivalent human gene in the human syntenic 14q3 region. A precise linkage map of the region is, therefore, of great interest since it will contribute to the genetic approach of the i.v. gene. Analysis of 242 back-cross progeny from Mus musculus (MAI) or spretus strains of mice and SI/Col mice has allowed mapping of the i.v. gene to a linkage group of eight markers. It includes four genes: Aat (alpha 1-antitrypsin), Ckb (creatine kinase, brain form), Crip (cysteine-rich intestinal protein), and Igh-C (immunoglobulin heavy chain constant region complex); three murine microsatellites: D12Mit6, D12Mit7, and D12Mit8; and one new marker, D12Mtp1, defined by a minisatellite human probe, pYNZ2. After analysis of the data by the LINKAGE program, the following multilocus map has been constructed: centromere-D12Mit6-6.9 cM-D12Mit7-1.7 cM-D12Mtp1-2.6 cM-Aat-5.0 cM-(Ckb, Igh-C)-0.4 cM-D12Mit8-0.4 cM-Crip-11.2 cM-i.v.-telomere. This map differs from the previous map in placing i.v. locus telomeric to Igh-C. D12Mit6 and D12Mit7 are now precisely mapped centromeric to the locus Aat. In addition, a new locus D12Mtp1 is located between Aat and D12Mit7.

Animals↗
PubMed1980

[Ehlers-Danolos syndrome: a disease of fibroblasts and collagen fibrils. Classification and electron-microscopic findings in five patients (author's transl)].

Five patients with Ehlers-Danlos syndrome (EDS) were classified according to clinical and genetic criteria and were examined by electron microscopy: two cases in Type I and one case each in Types II, III, and V were found. In all cases distinct ultrastructural changes were seen in the fibroblasts and the collagen fibrils whereas the elastic fibers were normal, as shown with special staining techniques. a) The fibroblasts were smaller, their cytoplasmic processes reduced in number and size, the endoplasmic reticulum was underdeveloped and their ribosome content was diminished. Also, cellular degeneration up to necrosis was found. In three cases intercellular substances were seen, possibly indicating a prefibrillar secretion product of the fibroblasts. b) The collagen fibrils revealed a defective lateral aggregation with disturbances of their thickness growth. Characteristic are abnormal fibrils with star-shaped cross profiles and marginal serrations in longitudinal sections. Their periodicity, however, remained normal. In three cases (Types I, I, and V) scattered giant fibrils were also present. Generally, the bundling of collagen fibrils into fibers seemed to be loosened. These findings were common to all various types of EDS. Therefore, a classification was not possible according to criteria of electron microscopy. Ehlers-Danlos syndrome is a disease of fibroblasts leading to changes of dermal collagen.

Adolescent↗
PubMed1975

[The narrow spinal canal - medicolegal aspects (author's transl)].

The constitutional anomayl of a narrow spinal canal was found in a neuroradiological department in 31 cases. The cervical stenosis can be defined in the following way: Inside diameter of cervical canal (anterior-posterior) in relation to diameter of vertebral body. In normal cases the quotient is over 1 - in pathological narrowing under 1. Clinical symptoms mainly appear from 45th year onwards, when reactive-degenerative changes increase the space problem. In wiplash injuries or other adequate cervical trauma 7 cases were seen and described with acute incomplete tetraplegia or/and multilocular lesions of cervical roots, resulting from cervical stenosis combined with degenerative changes in 6 patients. Myelography revealed multilocular deformities of the spinal subarachnoidal space in the abnormal narrow cervical canal. The referred cases were not complicated with forensic aspects. The prognosis quod sanationem was poor. A chronic cervical myelopathy results. Pretraumatic clinical alterations of cervical roots and/or the myelon in the referred cases were absent, existing in other patients. Predominantly men and hard working people with narrow cervical canal became ill. Early symptoms were pain in extremities. Dysesthesia and loss of sensation combined with signs of pyramidal lesion occured later. Defects in nerve roots sometimes overlayed the myelon symptoms. Unspecific CSF-Alterations were common. The EMG showed abnormalities in cases of root involvement. Operative treatment was tried to remove the reactive processes, but could not alter the constitutional anomaly. The resulting immobilisation of myelon and nerve roots involves in the case of trauma a direct mechanical lesion and secondary vascular complications via Arteria vertebralis, spinalis anterior and radicularis, namely in patients with degenerative alterations of the cervical spine, these including a further narrowing behind the constitutional anomaly. Our experience seems to recommend that more attention should be paid a cervical narrow spinal canal in medicolegal implications.

Adult↗