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At least 919 records · Page 51Linked to original sources
PubMed1997

Prenatal diagnosis of ventriculo-coronary communications in a second-trimester fetus using transvaginal and transabdominal color Doppler sonography.

We report on the prenatal diagnosis of ventriculo-coronary communication associated with pulmonary atresia and an intact interventricular septum. The diagnosis was made by transvaginal color Doppler sonography at 17 weeks' gestation and confirmed by transabdominal sonography at 19 weeks. Color Doppler demonstrated the communication between the distal hypoplastic right ventricle and the right coronary artery, with the course of this vessel situated along the outer heart wall. Spectral Doppler assessment showed bidirectional arterial flow in this vessel. Extracardiac skeletal anomalies (cleft hands and feet) were also detected and classified as an ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome. This led the parents to opt for termination of pregnancy. All findings were confirmed on autopsy. Using stereomicroscopy the malformations of the coronary system and main connections to the lumen of the right ventricle were additionally demonstrated. To our knowledge this is the first report on the identification of coronary artery malformations in a midtrimester fetus using transvaginal color Doppler. The early appearance enabled us to investigate the pathophysiological sequence of the combined defect. Further investigation might elucidate whether ventriculo-coronary communications arise secondary to pulmonary atresia and intact inter-ventricular septum, due to increased ventricular pressure, or are the primary defect leading to intrauterine pulmonary atresia or, indeed, whether both defects appear simultaneously.

Adult↗
PubMed1987

Developmental analysis of cephalic axial dysraphic disorders in arsenic-treated hamster embryos.

Parenteral injection of pregnant golden hamsters with inorganic arsenic salts early in gestation results, by term, in markedly elevated embryonic-fetal mortality (approximately equal to 50%) and, in surviving fetuses, a high (approximately equal to 90%) incidence of cephalic axial dysraphic disorders ("neural tube defects"), particularly exencephaly/anencephaly and encephaloceles. The present investigation traces the day by day development of these embryopathic effects of arsenic in the hamster with an emphasis on the pathogenesis of cephalic axial dysraphic disorders. Pregnant golden hamsters were given an intraperitoneal injection of sodium arsenate (20 mg/kg) on the 8th day (08.00) of their 16 day gestation period. Matched control dams were injected with an equivalent volume of distilled water by the same route and at the same stage of gestation. Experimental and control dams were sacrificed beginning 24 h after treatment and at regular daily intervals thereafter until term. Embryos and fetuses delivered from sacrificed dams were examined for abnormalities both grossly and histologically. In embryos delivered earliest after treatment (24-48 h) the principal deleterious effect of arsenic observed was retarded growth (elevation, approximation, and fusion) of the cephalic neural folds. This growth retardation ranged in severity among embryos. In the most severely afflicted there was a site wherein the opposing cephalic neural folds had completely failed to appose and fuse ("closure"). This failure of closure of all four tissue components of the neural folds (surface ectoderm, paraxial mesoderm, neural crest cells, neuroectoderm) resulted in a persistent dorsal opening in the head, i.e., cranioschisis aperta. The extent and appearance of this opening varied from a small, ovoid aperture in the dorsal midbrain (mesencephalic) region of the head to a widely open cleft involving the fore and hindbrain regions as well as the midbrain region. In less severely afflicted early embryos, the cephalic neural folds had elevated and met in the dorsal midline but had only incompletely fused, i.e., cranioschisis occulta. Microscopic study of these latter embryos revealed that in the affected region(s), complete closure of the surface ectoderm component of the neural folds had taken place, but only partial closure of the mesoderm, neural crest and neuroectoderm components. The different types of cephalic axial dysraphic disorders presenting in arsenic-treated fetuses delivered at later gestational stages (predominantly exencephaly and encephaloceles) could all be traced back and related to one or the other of these early forms of disturbed neurulation.

Abnormalities, Drug-Induced↗
PubMed2005

Mutation identification in a canine model of X-linked ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XHED), an inherited disease recognized in humans, mice, and cattle, is characterized by hypotrichosis, a reduced number or absence of sweat glands, and missing or malformed teeth. In a subset of affected individuals and animals, mutations in the EDA gene (formerly EDI), coding for ectodysplasin, have been found to cause this phenotype. Ectodysplasin is a homotrimeric transmembrane protein with an extracellular TNF-like domain, which has been shown to be involved in the morphogenesis of hair follicles and tooth buds during fetal development. Some human XHED patients also have concurrent immunodeficiency, due to mutations in the NF-kappaB essential modulator protein (IKBKG; formerly NEMO), which is also encoded on the X chromosome. In a breeding colony of dogs with XHED, immune system defects had been suspected because of frequent pulmonary infections and unexpected deaths resulting from pneumonia. To determine if defects in EDA or IKBKG cause XHED in the dogs, linkage analysis and sequencing experiments were performed. A polymorphic marker near the canine EDA gene showed significant linkage to XHED. The canine EDA gene was sequenced and a nucleotide substitution (G to A) in the splice acceptor site of intron 8 was detected in affected dogs. In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin.

Animals↗
PubMed1995

Mirror image duplication of the hands and feet: report of a sporadic case with multiple congenital anomalies.

Mirror image duplication of the hands and feet is a rare entity. Based on 3 previous reports, findings include nasal abnormalities, dimelia of ulna and fibula, tibial hypoplasia and mirror image duplication of hands and feet. We report on a sporadic case in which mirror image duplication was associated with multiple congenital anomalies. Although these cases may represent variable expression of the same dominantly transmitted complex polysyndactyly syndrome, it is possible that mirror image duplication of the hands and feet is a manifestation common to a number of distinct clinical entities. During limb bud development, duplication and aberrant positioning of the zone of polarizing activity in relation to the apical ectodermal ridge may account for the anatomic abnormalities of the hands and feet in these patients.

Abnormalities, Multiple↗
PubMed2001

Morphogenesis of prechordal plate and notochord requires intact Eph/ephrin B signaling.

Eph receptors and their ligands, the ephrins, mediate cell-to-cell signals implicated in the regulation of cell migration processes during development. We report the molecular cloning and tissue distribution of zebrafish transmembrane ephrins that represent all known members of the mammalian class B ephrin family. The degree of homology among predicted ephrin B sequences suggests that, similar to their mammalian counterparts, zebrafish B-ephrins can also bind promiscuously to several Eph receptors. The dynamic expression patterns for each zebrafish B-ephrin support the idea that these ligands are confined to interact with their receptors at the borders of their complementary expression domains. Zebrafish B-ephrins are expressed as early as 30% epiboly and during gastrula stages: in the germ ring, shield, prechordal plate, and notochord. Ectopic overexpression of dominant-negative soluble ephrin B constructs yields reproducible defects in the morphology of the notochord and prechordal plate by the end of gastrulation. Notably disruption of Eph/ephrin B signaling does not completely destroy structures examined, suggesting that cell fate specification is not altered. Thus abnormal morphogenesis of the prechordal plate and the notochord is likely a consequence of a cell movement defect. Our observations suggest Eph/ephrin B signaling plays an essential role in regulating cell movements during gastrulation.

Amino Acid Sequence↗
PubMedDate not supplied

Differential expression of two cell adhesion molecules, Ephrin-A5 and Integrin alpha6, during cranial neurulation in the chick embryo.

The formation of the neural tube (neurulation) depends on the physical properties of the cells and tissues both inside and outside the neural plate. One such important physical property is cell adhesion. Theoretical and biological evidence support a role for cell adhesion in neurulation, but few specific cell adhesion molecules have been identified during this process. Ephrin-A5 and Integrin alpha6 are two of the known genes encoding cell adhesion molecules that are likely to be directly involved in neurulation because neural tube defects result when they are knocked out in mice. Yet it remains unclear how they can act on the cell and tissue behaviors of neurulation, because their domains of expression in neurulating tissues have not been reported. We report here the detailed pattern of expression of these two cell adhesion molecules in the chick embryo throughout the stages of neurulation at the mRNA and protein level. We show that Ephrin-A5 and Integrin alpha6 are differentially expressed in the ectoderm, outside and inside the neural plate, respectively, and that they are both restricted to neurulation at cranial (brain) levels. We discuss the potential contribution of this differential expression to the cell adhesion mechanisms involved in cranial neurulation and anencephaly.

Animals↗
PubMed2003

Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by GATA-4 and -6.

Transcription factors GATA-4, -5, and -6 constitute an evolutionary conserved subfamily of vertebrate zinc finger regulators highly expressed in the developing heart and gut. Genetic evidence suggests that each protein is essential for embryonic development, but their exact functions are not fully elucidated. Moreover, because all three proteins share similar transcriptional properties in vitro, and because transcripts for two or more GATA genes are present in similar tissues, the molecular basis underlying in vivo specificity of GATA factors remains undefined. Knowledge of the exact cell types expressing each protein and identification of downstream targets would greatly help define their function. We have used high-resolution immunohistochemistry to precisely determine the cellular distribution of the GATA-4, -5, and -6 proteins in murine embryogenesis. The results reveal novel sites of expression in mesodermal and ectodermal cells. In particular, GATA-4 and -6 expression was closely associated with yolk sac vasculogenesis and early endoderm-mesoderm signaling. Additionally, GATA-6 was strongly expressed in the embryonic ectoderm, neural tube, and neural crest-derived cells. This pattern of expression closely paralled that of BMP-4, and the BMP-4 gene was identified as a direct downstream target for GATA-4 and -6. These findings offer new insight into the function of GATA-4 and -6 during early stages of embryogenesis and reveal the existence of a positive cross-regulatory loop between BMP-4 and GATA-4. They also raise the possibility that part of the early defects in GATA-4 and/or GATA-6 null embryos may be due to impaired BMP-4 signaling.

Base Sequence↗
PubMed1997

Neurulation: coming to closure.

Neurulation is a morphogenetic event par excellence. During this highly choreographed four-dimensional process, a flat sheet of ectoderm is transformed into an elongated tubular rudiment, the neural tube, which exhibits rostro-caudal and mediolateral regionalization. Many tissues interact during neurulation to induce and regionalize the neuroectoderm and to produce the morphogenetic forces that drive neurulation. Such forces are generated by fundamental cell behaviors such as changes in cell shape, position and number. In addition, morphoregulatory molecules expressed during neurulation underlie induction and patterning of the forming neuraxis. Despite recent advances in our understanding of neurulation, neural tube defects continue to be a major health care concern. Further research, utilizing a panoply of approaches, is necessary to resolve this issue. Thus, although we are beginning to come to closure in terms of understanding the cellular and molecular mechanisms responsible for normal neural tube formation, 'coming to closure' is exactly the problem that requires resolution to prevent these devastating birth defects.

Animals↗
PubMed2001

Zebrafish wnt8 encodes two wnt8 proteins on a bicistronic transcript and is required for mesoderm and neurectoderm patterning.

In vertebrates, wnt8 has been implicated in the early patterning of the mesoderm. To determine directly the embryonic requirements for wnt8, we generated a chromosomal deficiency in zebrafish that removes the bicistronic wnt8 locus. We report that homozygous mutants exhibit pronounced defects in dorso-ventral mesoderm patterning and in the antero-posterior neural pattern. Despite differences in their signaling activities, either coding region of the bicistronic RNA can rescue the deficiency phenotype. Specific interference of wnt8 translation by morpholino antisense oligomers phenocopies the deficiency, and interference with wnt8 translation in ntl and spt mutants produces embryos lacking trunk and tail. These data demonstrate that the zebrafish wnt8 locus is required during gastrulation to pattern both the mesoderm and the neural ectoderm properly.

Amino Acid Sequence↗
PubMed2001

Hyper IgM syndrome: the other side of the coin.

The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene that prevent it from delivering an activation signal to antigen-presenting cells via CD40. Over the past year, defects in molecules involved in CD40 signaling have been shown to cause other forms of hyper IgM. These newly identified defects emphasize the importance of interaction between CD40 and its ligand in immunity and the role of these molecules in the pathogenesis of immune deficiency. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.

Antigen-Presenting Cells↗
PubMed1976

Embryological study of a T/t locus mutation (tw73) affecting trophectoderm development.

Mouse embryos homozygous for the recessive lethal mutation tw73 show specific defects in trophectoderm shortly after implantation. The trophectoderm and ectoplacental cone fail to form the usual close association with the uterine decidua, and proliferation is markedly reduced. The embryo proper ceases to develop beyond the two-layered stage and degenerates and dies within 5 days of implantation.

Animals↗
PubMed1997

Embryonic morphogenesis signaling pathway mediated by JNK targets the transcription factor JUN and the TGF-beta homologue decapentaplegic.

The dorsal surface of the Drosophila embryo is formed by the migration of the lateral epithelial cells to cover the amnioserosa. The Drosophila cJun-N-terminal kinase (DJNK) is essential for this process. Mutations in DJNK or the DJNK activator hemipterous (HEP) lead to incomplete dorsal closure, resulting in a hole in the dorsal cuticle. The molecules downstream of DJNK in this signaling pathway have not been established. Here we demonstrate that the basket1 (bsk1) mutation of DJNK causes decreased interaction with DJUN. Expression of decapentaplegic (DPP), a TGF-beta homologue, in the leading edge of the dorsal epithelium, is identified as a genetic target of the JNK pathway. A constitutive allele of JUN is able to rescue the dorsal closure defect of bsk1 and restores DPP expression. Furthermore, ectopic DPP rescues the defects in dorsal closure caused by bsk1. These data indicate that the interaction of DJNK with DJUN contributes to the dorsal closure signaling pathway and targets DPP expression.

Activating Transcription Factor 2↗
PubMed1991

Morphogenesis of retinoic acid-induced postaxial polydactyly in mice.

Previous experiments have demonstrated that oral administration of retinoic acid to ICR mice on day 10 of gestation results in an enhanced expression of postaxial polydactyly of the forelimbs. In the present investigations, the development of the limbs from the time of treatment until the appearance of the defect on day 14 were studied at 12- to 24-hr intervals with histological and vital staining technics. A diffuse cytotoxicity in the central proximal mesoderm was noted with a safranin-toluidine blue stain 12 h after treatment which then peaked 24 hr after treatment. Treated limbs stained with Nile blue sulfate showed a significant increase of necrotic mesodermal cells in the foyer preaxial primaire, foyer marginal I and foyer marginal V when compared to the respective control group. The treated postaxial ectoderm was more hyperplastic than was the control ectoderm on day 12. The treated group developed a squarish bulge on the postaxial boundary of the fifth digital ray on day 14 that was larger than those of the controls. Most of the controls had bulges that were completely necrotic. The treated group also had some completely necrotic bulges but a large number of the treated fetuses had bulges characterized as being less than 60% necrotic.

Abnormalities, Drug-Induced↗
PubMed2006

Immunodeficiencies with autoimmune consequences.

Far from being mutually exclusive, immunodeficiency and autoimmunity may occur simultaneously. During the last years, analysis of Autoimmune Polyendocrinopathy--Candidiasis--Ectodermal Dystrophy (APECED) and Immunodysregulation--Polyendocrinopathy--Enteropathy--X-linked (IPEX), two rare monogenic forms of immunodeficiency associated with autoimmunity, has led to the identification of Auto Immune Regulator (AIRE) and Forkhead Box P3 (FOXP3), essential transcriptional regulators, involved in central tolerance and peripheral immune homeostasis, respectively. Characterization of the molecular and cellular mechanisms involved in APECED, and recognition that AIRE expression is sustained by effective thymopoiesis, has recently allowed to define that the autoimmunity of Omenn syndrome, a combined immunodeficiency due to defects of V(D)J recombination, also results from defective expression of AIRE. The implications of identification of the basis of autoimmunity in these rare forms of immunodeficiency have important implications for a better understanding of more common autoimmune disorders, and for development of novel therapeutic approaches.

Animals↗
PubMedDate not supplied

Cell-autonomous action of zebrafish spt-1 mutation in specific mesodermal precursors.

In zebrafish, as in Xenopus, the well-orchestrated cell movements of gastrulation can be dissected into several components, including epiboly, involution, convergence and extension. Embryos homozygous for the recessive lethal mutation spt-1(b104) or 'spadetail' have a complex set of defects in the trunk of the embryo that may arise secondarily after loss of one of these movements, convergence, from those precursors that would normally have given rise to trunk somitic mesoderm. We have now tested this hypothesis by transplanting cells between wild-type and mutant embryos, to identify the cells that spt-1 affects directly. Our results show that the mutation autonomously affects only those mesodermal precursors located along the lateral margin of the early gastrula blastoderm. Other mesodermal cells and all ectodermal precursors seem not to require function of the wild-type gene. Our findings reveal an unexpectedly delicate genetic control of vertebrate gastrulation.

Animals↗
PubMed2005

Laminin alpha5 is required for dental epithelium growth and polarity and the development of tooth bud and shape.

In tooth development, the oral ectoderm and mesenchyme coordinately and reciprocally interact through the basement membrane for their growth and differentiation to form the proper shape and size of the tooth. Laminin alpha5 subunit-containing laminin-10/11 (LM-511/521) is the major laminin in the tooth germ basement membrane. Here, we have examined the role of laminin alpha5 (Lama5) in tooth development using laminin alpha5-null mouse primary dental epithelium and tooth germ organ cultures. Lama5-null mice develop a small tooth germ with defective cusp formation and have reduced proliferation of dental epithelium. Also, cell polarity and formation of the monolayer of the inner dental epithelium are disturbed. The enamel knot, a signaling center for tooth germ development, is defective, and there is a significant reduction of Shh and Fgf4 expression in the dental epithelium. In the absence of laminin alpha5, the basement membrane in the inner dental epithelium becomes discontinuous. In normal mice, integrin alpha6beta4, a receptor for laminin alpha5, is strongly localized at the basal layer of the epithelium, whereas in mutant mice, integrin alpha6beta4 is expressed around the cell surface. In primary dental epithelium culture, laminin-10/11 promotes cell growth, spreading, and filopodia-like microspike formation. This promotion is inhibited by anti-integrin alpha6 and beta4 antibodies and by phosphatidylinositol 3-kinase inhibitors and dominant negative Rho-GTPase family proteins Cdc42 and Rac. In organ culture, anti-integrin alpha6 antibody and wortmannin reduce tooth germ size and shape. Our studies demonstrate that laminin alpha5 is required for the proliferation and polarity of basal epithelial cells and suggest that the interaction between laminin-10/11-integrin alpha6beta4 and the phosphatidylinositol 3-kinase-Cdc42/Rac pathways play an important role in determining the size and shape of tooth germ.

Animals↗
PubMed2004

Commitment and response to inductive signals of primary mesenchyme cells of the sea urchin embryo.

In the sea urchin embryo, primary mesenchyme cells (PMC) are committed to produce the larval skeleton, although their behavior and skeleton production are influenced by signals from the embryonic environment. Results from our recent studies showed that perturbation of skeleton development, by interfering with ectoderm-extracellular matrix (ECM) interactions, is linked to a reduction in the gene expression of a transforming growth factor (TGF)-beta growth factor, Pl-univin, suggesting a reduction in the blastocoelic amounts of the protein and its putative involvement in signaling events. In the present study, we examined PMC competence to respond to environmental signals in a validated skeleton perturbation model in Paracentrotus lividus. We found that injection of blastocoelic fluid (BcF), obtained from normal embryos, into the blastocoelic cavity of skeleton-defective embryos rescues skeleton development. In addition, PMC from skeleton-defective embryos transplanted into normal or PMC-less blastula embryos are able to position in correct regions of the blastocoel and to engage spicule elongation and patterning. Taken together, these results demonstrate that PMC commitment to direct skeletogenesis is maintained in skeleton perturbed embryos and confirm the role played by inductive signals in regulating skeleton growth and shape.

Animals↗