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Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations.
Gray RS, Wilm TP, Smith J, Bagnat M, Dale RM, Topczewski J, Johnson SL, Solnica-Krezel L
(2014) Dev Biol 386: 72-85
MeSH Terms: Alleles, Animals, Collagen Type VIII, Crosses, Genetic, Gene Expression Regulation, Developmental, In Situ Hybridization, Meiosis, Microscopy, Confocal, Microscopy, Electron, Transmission, Mutation, Notochord, Osteoblasts, Protein-Lysine 6-Oxidase, Spine, Time Factors, Zebrafish
Show Abstract · Added March 20, 2014
Congenital vertebral malformations (CVM) occur in 1 in 1000 live births and in many cases can cause spinal deformities, such as scoliosis, and result in disability and distress of affected individuals. Many severe forms of the disease, such as spondylocostal dystostosis, are recessive monogenic traits affecting somitogenesis, however the etiologies of the majority of CVM cases remain undetermined. Here we demonstrate that morphological defects of the notochord in zebrafish can generate congenital-type spine defects. We characterize three recessive zebrafish leviathan/col8a1a mutant alleles ((m531, vu41, vu105)) that disrupt collagen type VIII alpha1a (col8a1a), and cause folding of the embryonic notochord and consequently adult vertebral column malformations. Furthermore, we provide evidence that a transient loss of col8a1a function or inhibition of Lysyl oxidases with drugs during embryogenesis was sufficient to generate vertebral fusions and scoliosis in the adult spine. Using periodic imaging of individual zebrafish, we correlate focal notochord defects of the embryo with vertebral malformations (VM) in the adult. Finally, we show that bends and kinks in the notochord can lead to aberrant apposition of osteoblasts normally confined to well-segmented areas of the developing vertebral bodies. Our results afford a novel mechanism for the formation of VM, independent of defects of somitogenesis, resulting from aberrant bone deposition at regions of misshapen notochord tissue.
Copyright © 2013 Elsevier Inc. All rights reserved.
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16 MeSH Terms
The feelgood mutation in zebrafish dysregulates COPII-dependent secretion of select extracellular matrix proteins in skeletal morphogenesis.
Melville DB, Montero-Balaguer M, Levic DS, Bradley K, Smith JR, Hatzopoulos AK, Knapik EW
(2011) Dis Model Mech 4: 763-76
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Bone and Bones, Branchial Region, COP-Coated Vesicles, Cartilage, Chondrocytes, Collagen Type II, Craniofacial Abnormalities, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Extracellular Matrix Proteins, Gene Knockdown Techniques, Genetic Loci, Glycosaminoglycans, Melanosomes, Molecular Sequence Data, Morphogenesis, Mutation, Notochord, Protein Transport, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added November 13, 2012
Craniofacial and skeletal dysmorphologies account for the majority of birth defects. A number of the disease phenotypes have been attributed to abnormal synthesis, maintenance and composition of extracellular matrix (ECM), yet the molecular and cellular mechanisms causing these ECM defects remain poorly understood. The zebrafish feelgood mutant manifests a severely malformed head skeleton and shortened body length due to defects in the maturation stage of chondrocyte development. In vivo analyses reveal a backlog of type II and type IV collagens in rough endoplasmic reticulum (ER) similar to those found in coat protein II complex (COPII)-deficient cells. The feelgood mutation hinders collagen deposition in the ECM, but trafficking of small cargos and other large ECM proteins such as laminin to the extracellular space is unaffected. We demonstrate that the zebrafish feelgood mutation causes a single amino acid substitution within the DNA-binding domain of transcription factor Creb3l2. We show that Creb3l2 selectively regulates the expression of genes encoding distinct COPII proteins (sec23a, sec23b and sec24d) but find no evidence for its regulation of sec24c expression. Moreover, we did not detect activation of ER stress response genes despite intracellular accumulation of collagen and prominent skeletal defects. Promoter trans-activation assays show that the Creb3l2 feelgood variant is a hypomorphic allele that retains approximately 50% of its transcriptional activity. Transgenic rescue experiments of the feelgood phenotype restore craniofacial development, illustrating that a precise level of Creb3l2 transcriptional activity is essential for skeletogenesis. Our results indicate that Creb3l2 modulates the availability of COPII machinery in a tissue- and cargo-specific manner. These findings could lead to a better understanding of the etiology of human craniofacial and skeletal birth defects as well as adult-onset diseases that are linked to dysregulated ECM deposition, such as arthritis, fibrosis or osteoporosis.
2 Communities
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25 MeSH Terms
Isolation and characterization of node/notochord-like cells from mouse embryonic stem cells.
Winzi MK, Hyttel P, Dale JK, Serup P
(2011) Stem Cells Dev 20: 1817-27
MeSH Terms: Animals, Antigens, Differentiation, Benzamides, Cell Differentiation, Cell Line, Cell Proliferation, Chick Embryo, Dioxoles, Embryonic Stem Cells, Green Fluorescent Proteins, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Intercellular Signaling Peptides and Proteins, Mice, Notochord, Organizers, Embryonic, Peptide Hormones, Pyrroles, Receptors, Growth Factor, Recombinant Fusion Proteins, Signal Transduction, Tissue Culture Techniques, Transplantation, Heterologous
Show Abstract · Added May 13, 2013
The homeobox gene Noto is expressed in the node and its derivative the notochord. Here we use a targeted Noto-GFP reporter to isolate and characterize node/notochord-like cells derived from mouse embryonic stem cells. We find very few Noto-expressing cells after spontaneous differentiation. However, the number of Noto-expressing cells was increased when using Activin A to induce a Foxa2- and Brachyury-expressing progenitor population, whose further differentiation into Noto-expressing cells was improved by simultaneous inhibition of BMP, Wnt, and retinoic acid signaling. Noto-GFP(+) cells expressed the node/notochord markers Noto, Foxa2, Shh, Noggin, Chordin, Foxj1, and Brachyury; showed a vacuolarization characteristic of notochord cells; and can integrate into midline structures when grafted into Hensen's node of gastrulating chicken embryos. The ability to generate node/notochord-like cells in vitro will aid the biochemical characterization of these developmentally important structures.
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23 MeSH Terms
Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.
Sommer J, Itani DM, Homlar KC, Keedy VL, Halpern JL, Holt GE, Schwartz HS, Coffin CM, Kelley MJ, Cates JM
(2010) J Pathol 220: 608-17
MeSH Terms: Adolescent, Adult, Aged, Biomarkers, Tumor, Bone Neoplasms, Child, Child, Preschool, Chondrosarcoma, Chordoma, Cyclin-Dependent Kinase Inhibitor p16, Female, Humans, Male, Middle Aged, Neoplasm Proteins, Notochord, Phosphorylation, Prognosis, Purine-Nucleoside Phosphorylase, Receptor, IGF Type 1, Signal Transduction, Survival Analysis, Tissue Array Analysis, Young Adult
Show Abstract · Added March 15, 2013
Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.
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24 MeSH Terms
Phospholipase D1 is required for angiogenesis of intersegmental blood vessels in zebrafish.
Zeng XX, Zheng X, Xiang Y, Cho HP, Jessen JR, Zhong TP, Solnica-Krezel L, Brown HA
(2009) Dev Biol 328: 363-76
MeSH Terms: 1-Butanol, Animals, Animals, Genetically Modified, Body Patterning, Cell Differentiation, Embryo, Nonmammalian, Liver, Neovascularization, Physiologic, Notochord, Phosphatidic Acids, Phospholipase D, Somites, Zebrafish, Zebrafish Proteins
Show Abstract · Added March 19, 2013
Phospholipase D (PLD) hydrolyzes phosphatidylcholine to generate phosphatidic acid and choline. Studies in cultured cells and Drosophila melanogaster have implicated PLD in the regulation of many cellular functions, including intracellular vesicle trafficking, cell proliferation and differentiation. However, the function of PLD in vertebrate development has not been explored. Here we report cloning and characterization of a zebrafish PLD1 (pld1) homolog. Like mammalian PLDs, zebrafish Pld1 contains two conservative HKD motifs. Maternally contributed pld1 transcripts are uniformly distributed in early embryo. Localized expression of pld1 is observed in the notochord during early segmentation, in the somites during later segmentation and in the liver at the larval stages. Studies in intact and cell-free preparations demonstrate evolutionary conservation of regulation. Inhibition of Pld1 expression using antisense morpholino oligonucleotides (MO) interfering with the translation or splicing of pld1 impaired intersegmental vessel (ISV) development. Incubating embryos with 1-butanol, which diverts production of phosphatidic acid to a phosphatidylalcohol, caused similar ISV defects. To determine where Pld1 is required for ISV development we performed transplantation experiments. Analyses of the mosaic Pld1 deficient embryos showed partial suppression of ISV defects in the segments containing transplanted wild-type notochord cells but not in the ones containing wild-type somitic cells. These results provide the first evidence that function of Pld1 in the developing notochord is essential for vascular development in vertebrates.
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14 MeSH Terms
Aberrant Bmp signaling and notochord delamination in the pathogenesis of esophageal atresia.
Li Y, Litingtung Y, Ten Dijke P, Chiang C
(2007) Dev Dyn 236: 746-54
MeSH Terms: Animals, Bone Morphogenetic Protein 7, Bone Morphogenetic Proteins, Carrier Proteins, Digestive System Abnormalities, Esophageal Atresia, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Models, Biological, Notochord, Rats, Signal Transduction, Transforming Growth Factor beta
Show Abstract · Added January 23, 2013
Human foregut malformation known as esophageal atresia with tracheoesophageal fistula (EA/TEF) occurs in 1 in 4,000 live births with unknown etiology. We found that mice lacking Noggin (Nog(-/-)) displayed Type C EA/TEF, the most common form in humans, and notochordal defects strikingly similar to the adriamycin-induced rat EA/TEF model. In accord with esophageal atresia, Nog(-/-) embryos displayed reduction in the dorsal foregut endoderm, which was associated with reduced adhesion and disrupted basement membrane. However, significant apoptosis in the Nog(-/-) dorsal foregut was not observed. Instead, non-notochordal, likely endodermal, cells were found in Nog(-/-) notochord, suggesting that Noggin function is required in the notochordal plate for its proper delamination from the dorsal foregut. Notably, ablating Bmp7 function in Nog(-/-) embryos rescued EA/TEF and notochord branching defects, establishing a critical role of Noggin-mediated Bmp7 antagonism in EA/TEF pathogenesis.
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17 MeSH Terms
Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.
Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, Nakashima M, Joyner AL
(2000) Development 127: 1593-605
MeSH Terms: Abnormalities, Multiple, Alleles, Animals, Binding Sites, Brain, COS Cells, DNA, DNA-Binding Proteins, Diencephalon, Embryonic and Fetal Development, Extremities, Gene Expression, Hedgehog Proteins, Humans, Kruppel-Like Transcription Factors, Lung, Mice, Mice, Transgenic, Mutagenesis, Nerve Tissue Proteins, Notochord, Nuclear Proteins, Oncogene Proteins, Proteins, Repressor Proteins, Signal Transduction, Spinal Cord, Trans-Activators, Transcription Factors, Xenopus Proteins, Zinc Finger Protein GLI1, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3, Zinc Fingers
Show Abstract · Added December 6, 2018
The secreted factor Sonic hedgehog (SHH) is both required for and sufficient to induce multiple developmental processes, including ventralization of the CNS, branching morphogenesis of the lungs and anteroposterior patterning of the limbs. Based on analogy to the Drosophila Hh pathway, the multiple GLI transcription factors in vertebrates are likely to both transduce SHH signaling and repress Shh transcription. In order to discriminate between overlapping versus unique requirements for the three Gli genes in mice, we have produced a Gli1 mutant and analyzed the phenotypes of Gli1/Gli2 and Gli1/3 double mutants. Gli3(xt) mutants have polydactyly and dorsal CNS defects associated with ectopic Shh expression, indicating GLI3 plays a role in repressing Shh. In contrast, Gli2 mutants have five digits, but lack a floorplate, indicating that it is required to transduce SHH signaling in some tissues. Remarkably, mice homozygous for a Gli1(zfd )mutation that deletes the exons encoding the DNA-binding domain are viable and appear normal. Transgenic mice expressing a GLI1 protein lacking the zinc fingers can not induce SHH targets in the dorsal brain, indicating that the Gli1(zfd )allele contains a hypomorphic or null mutation. Interestingly, Gli1(zfd/zfd);Gli2(zfd/+), but not Gli1(zfd/zfd);Gli3(zfd/+) double mutants have a severe phenotype; most Gli1(zfd/zfd);Gli2(zfd/+) mice die soon after birth and all have multiple defects including a variable loss of ventral spinal cord cells and smaller lungs that are similar to, but less extreme than, Gli2(zfd/zfd) mutants. Gli1/Gli2 double homozygous mutants have more extreme CNS and lung defects than Gli1(zfd/zfd);Gli2(zfd/+) mutants, however, in contrast to Shh mutants, ventrolateral neurons develop in the CNS and the limbs have 5 digits with an extra postaxial nubbin. These studies demonstrate that the zinc-finger DNA-binding domain of GLI1 protein is not required for SHH signaling in mouse. Furthermore, Gli1 and Gli2, but not Gli1 and Gli3, have extensive overlapping functions that are likely downstream of SHH signaling.
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MeSH Terms
Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.
Ericson J, Morton S, Kawakami A, Roelink H, Jessell TM
(1996) Cell 87: 661-73
MeSH Terms: Animals, Body Patterning, Cell Differentiation, Cell Division, Central Nervous System, Chick Embryo, Embryonic Induction, Hedgehog Proteins, Interneurons, Models, Biological, Motor Neurons, Notochord, Proteins, Stem Cells, Time Factors, Trans-Activators
Show Abstract · Added November 9, 2010
Antibodies that block Sonic Hedgehog (SHH) signaling have been used to show that SHH activity is required for the induction of floor plate differentiation by the notochord and independently for the induction of motor neurons by both the notochord and midline neural cells. Motor neuron generation depends on two critical periods of SHH signaling: an early period during which naive neural plate cells are converted into ventralized progenitors and a late period that extends well into S phase of the final progenitor cell division, during which SHH drives the differentiation of ventralized progenitors into motor neurons. The ambient SHH concentration during the late period determines whether ventralized progenitors differentiate into motor neurons or interneurons, thus defining the pattern of neuronal cell types generated in the neural tube.
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16 MeSH Terms
Ventral neural cadherin, a novel cadherin expressed in a subset of neural tissues in the zebrafish embryo.
Franklin JI, Sargent TD
(1996) Dev Dyn 206: 121-30
MeSH Terms: Animals, Base Sequence, Blotting, Northern, Blotting, Southern, Body Patterning, Cadherins, Central Nervous System, Cloning, Molecular, Gene Expression Regulation, Developmental, In Situ Hybridization, Molecular Sequence Data, Mutation, Notochord, Sequence Homology, Amino Acid, Somites, Transcription, Genetic, Zebrafish
Show Abstract · Added March 20, 2014
Cadherins are calcium-binding transmembrane glycoproteins that are important mediators of cell-cell association. Here we describe a novel member of this gene family, zebrafish ventral neural cadherin (VN-cad). Multiple VN-cad transcripts are first detectable by Northern blots at 60% epiboly. In the developing neural tube, VN-cad RNA is first found in the neuroectoderm, directly above the notochord, and later was localized to the neural keel. At the 20-somite stage, VN-cad transcripts are confined to the ventral neural tube, otic vesicle, midbrain, and diencephelon. Transcription of VN-cad RNA continues in adult fish. The embryonic pattern of expression is not significantly disrupted in cyclops or no tail mutants, which lack the floor plate and notochord, respectively. Therefore, neither of these structures is absolutely required for VN-cad expression. The localized pattern of VN-cad expression suggests a possible role for this adhesion molecule in the initial formation and subsequent differentiation of the central nervous system.
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17 MeSH Terms
Control of cell pattern in the neural tube: motor neuron induction by diffusible factors from notochord and floor plate.
Yamada T, Pfaff SL, Edlund T, Jessell TM
(1993) Cell 73: 673-86
MeSH Terms: Animals, Base Sequence, Cell Communication, Cell Differentiation, Chick Embryo, Molecular Sequence Data, Motor Neurons, Nervous System, Notochord, Quail
Show Abstract · Added July 30, 2010
The identity of cell types generated along the dorsoventral axis of the neural tube depends on inductive signals that derive from both mesodermal and neural cells. To define the nature of these signals, we have analyzed the differentiation of cells in neural plate explants. Motor neurons and neural crest cells differentiate in vitro from appropriate regions of the neural plate, indicating that the specification of cell fate along the dorsoventral axis of the neural tube begins at the neural plate stage. Motor neuron differentiation can be induced by a diffusible factor that derives initially from the notochord and later from floor plate cells. By contrast, floor plate induction requires contact with the notochord. Thus, the identity and patterning of neural cell types appear to involve distinct contact-mediated and diffusible signals from the notochord and floor plate.
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10 MeSH Terms