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Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway.
Cox NJ, Unlu G, Bisnett BJ, Meister TR, Condon BM, Luo PM, Smith TJ, Hanna M, Chhetri A, Soderblom EJ, Audhya A, Knapik EW, Boyce M
(2018) Biochemistry 57: 91-107
MeSH Terms: Acetylglucosamine, Acylation, Animals, COP-Coated Vesicles, Cell Line, Collagen, Craniofacial Abnormalities, Disease Models, Animal, Glycosylation, Humans, Organelles, Protein Conformation, Protein Processing, Post-Translational, Protein Transport, Vertebrates, Vesicular Transport Proteins, Zebrafish
Show Abstract · Added March 15, 2018
The COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities, and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic, or pathological cues. Several COPII proteins are modified by O-linked β-N-acetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular, and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein-protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of SEC23A, an essential COPII component, are required for its function in human cells and vertebrate development, because mutation of these sites impairs SEC23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway.
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17 MeSH Terms
Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients.
Humphreys R, Zheng W, Prince LS, Qu X, Brown C, Loomes K, Huppert SS, Baldwin S, Goudy S
(2012) Hum Mol Genet 21: 1374-83
MeSH Terms: Alagille Syndrome, Animals, Blotting, Western, Calcium-Binding Proteins, Cells, Cultured, Craniofacial Abnormalities, Embryo, Mammalian, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Integrases, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Membrane Proteins, Mesoderm, Mice, Mice, Inbred C57BL, Mice, Knockout, Morphogenesis, Neural Crest, Phenotype, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Serrate-Jagged Proteins, Wnt1 Protein
Show Abstract · Added December 16, 2011
JAGGED1 mutations cause Alagille syndrome, comprising a constellation of clinical findings, including biliary, cardiac and craniofacial anomalies. Jagged1, a ligand in the Notch signaling pathway, has been extensively studied during biliary and cardiac development. However, the role of JAGGED1 during craniofacial development is poorly understood. Patients with Alagille syndrome have midface hypoplasia giving them a characteristic 'inverted V' facial appearance. This study design determines the requirement of Jagged1 in the cranial neural crest (CNC) cells, which encompass the majority of mesenchyme present during craniofacial development. Furthermore, with this approach, we identify the autonomous and non-autonomous requirement of Jagged1 in a cell lineage-specific approach during midface development. Deleting Jagged1 in the CNC using Wnt1-cre; Jag1 Flox/Flox recapitulated the midfacial hypoplasia phenotype of Alagille syndrome. The Wnt1-cre; Jag1 Flox/Flox mice die at postnatal day 30 due to inability to masticate owing to jaw misalignment and poor occlusion. The etiology of midfacial hypoplasia in the Wnt1-cre; Jag1 Flox/Flox mice was a consequence of reduced cellular proliferation in the midface, aberrant vasculogenesis with decreased productive vessel branching and reduced extracellular matrix by hyaluronic acid staining, all of which are associated with midface anomalies and aberrant craniofacial growth. Deletion of Notch1 from the CNC using Wnt1-cre; Notch1 F/F mice did not recapitulate the midface hypoplasia of Alagille syndrome. These data demonstrate the requirement of Jagged1, but not Notch1, within the midfacial CNC population during development. Future studies will investigate the mechanism in which Jagged1 acts in a cell autonomous and cell non-autonomous manner.
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28 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.
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25 MeSH Terms
Functional interaction between Foxd3 and Pax3 in cardiac neural crest development.
Nelms BL, Pfaltzgraff ER, Labosky PA
(2011) Genesis 49: 10-23
MeSH Terms: Animals, Craniofacial Abnormalities, Embryo Loss, Forkhead Transcription Factors, Mice, Mice, Mutant Strains, Neural Crest, PAX3 Transcription Factor, Paired Box Transcription Factors, Repressor Proteins, Sequence Deletion, Stem Cells, Thymus Gland, Truncus Arteriosus, Persistent
Show Abstract · Added March 31, 2011
The transcription factors Foxd3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of Foxd3 cause marked defects in most NC derivatives, but neither loss of both Foxd3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific Foxd3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. Foxd3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for Foxd3 and Pax3 in cardiac NC progenitors. Foxd3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development.
Copyright © 2010 Wiley-Liss, Inc.
1 Communities
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14 MeSH Terms
Inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway.
Sarmah B, Wente SR
(2010) Proc Natl Acad Sci U S A 107: 19921-6
MeSH Terms: Animals, Cell Movement, Craniofacial Abnormalities, Embryo, Mammalian, Embryonic Development, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Hedgehog Proteins, Inositol Phosphates, Mice, NIH 3T3 Cells, Neural Crest, Phosphotransferases (Phosphate Group Acceptor), Signal Transduction, Somites, Zebrafish, Zebrafish Proteins
Show Abstract · Added March 7, 2014
Inositol phosphate (IP) kinases constitute an emerging class of cellular kinases linked to multiple cellular activities. Here, we report a previously uncharacterized cellular function in Hedgehog (Hh) signaling for the IP kinase designated inositol hexakisphosphate kinase-2 (IP6K2) that produces diphosphoryl inositol phosphates (PP-IPs). In zebrafish embryos, IP6K2 activity was required for normal development of craniofacial structures, somites, and neural crest cells. ip6k2 depletion in both zebrafish and mammalian cells also inhibited Hh target gene expression. Inhibiting IP(6) kinase activity using N(2)-(m-(trifluoromethy)lbenzyl) N(6)-(p-nitrobenzyl)purine (TNP) resulted in altered Hh signal transduction. In zebrafish, restoring IP6K2 levels with exogenous ip6k2 mRNA reversed the effects of IP6K2 depletion. Furthermore, overexpression of ip6k2 in mammalian cells enhanced the Hh pathway response, suggesting IP6K2 is a positive regulator of Hh signaling. Perturbations from IP6K2 depletion or TNP were reversed by overexpressing smoM2, gli1, or ip6k2. Moreover, the inhibitory effect of cyclopamine was reversed by overexpressing ip6k2. This identified roles for the inositol kinase pathway in early vertebrate development and tissue morphogenesis, and in Hh signaling. We propose that IP6K2 activity is required at the level or downstream of Smoothened but upstream of the transcription activator Gli1.
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17 MeSH Terms
Fgf8 is required for anterior heart field development.
Ilagan R, Abu-Issa R, Brown D, Yang YP, Jiao K, Schwartz RJ, Klingensmith J, Meyers EN
(2006) Development 133: 2435-45
MeSH Terms: Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Branchial Region, Cardiovascular Abnormalities, Craniofacial Abnormalities, Embryo, Mammalian, Endoderm, Extracellular Signal-Regulated MAP Kinases, Fibroblast Growth Factor 8, Gene Expression Regulation, Developmental, Genes, Reporter, Heart, Homeodomain Proteins, In Situ Hybridization, Mesoderm, Mice, Mice, Knockout, Neural Crest, Signal Transduction, Transcription Factors
Show Abstract · Added August 28, 2017
In the mouse embryo, the splanchnic mesodermal cells of the anterior heart field (AHF) migrate from the pharynx to contribute to the early myocardium of the outflow tract (OT) and right ventricle (RV). Recent studies have attempted to distinguish the AHF from other precardiac populations, and to determine the genetic and molecular mechanisms that regulate its development. Here, we have used an Fgf8lacZ allele to demonstrate that Fgf8 is expressed within the developing AHF. In addition, we use both a hypomorphic Fgf8 allele (Fgf8neo) and Cre-mediated gene ablation to show that Fgf8 is essential for the survival and proliferation of the AHF. Nkx2.5Cre is expressed in the AHF, primary heart tube and pharyngeal endoderm, while TnT-Cre is expressed only within the specified heart tube myocardium. Deletion of Fgf8 by Nkx2.5Cre results in a significant loss of the Nkx2.5Cre lineage and severe OT and RV truncations by E9.5, while the remaining heart chambers (left ventricle and atria) are grossly normal. These defects result from significant decreases in cell proliferation and aberrant cell death in both the pharyngeal endoderm and splanchnic mesoderm. By contrast, ablation of Fgf8 in the TnT-Cre domain does not result in OT or RV defects, providing strong evidence that Fgf8 expression is crucial in the pharyngeal endoderm and/or overlying splanchnic mesoderm of the AHF at a stage prior to heart tube elongation. Analysis of downstream signaling components, such as phosphorylated-Erk and Pea3, identifies the AHF splanchnic mesoderm itself as a target for Fgf8 signaling.
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21 MeSH Terms
Expression and regulation of chicken fibroblast growth factor homologous factor (FHF)-4 during craniofacial morphogenesis.
Muñoz-Sanjuán I, Cooper MK, Beachy PA, Fallon JF, Nathans J
(2001) Dev Dyn 220: 238-45
MeSH Terms: Animals, Chick Embryo, Craniofacial Abnormalities, Facial Bones, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, In Situ Hybridization, Mutation, Signal Transduction, Skull, Tretinoin
Show Abstract · Added March 5, 2014
Fibroblast growth factor homologous factors (FHFs) have been implicated in limb and nervous system development. In this paper we describe the expression of the cFHF-4 gene during chicken craniofacial development. cFHF-4 is expressed in the mesenchyme of the frontonasal process, and in the mesenchyme and ectoderm of the mandibular processes. The expression of cFHF-4 and other genes implicated in facial patterning have been analyzed in talpid(2) embryos or in the presence of exogenous retinoic acid. Talpid(2) mutants show abnormal patterns of gene expression, including up-regulation of cFHF-4 in the developing face, which correlate with defects in cartilage formation. By contrast, expression of cFHF-4 in the developing face is strongly downregulated by teratogenic doses of all-trans retinoic acid in a dose-dependent manner. Low levels of retinoic acid that produce distal upper beak truncations do not affect cShh, c-Patched-1, or c-Bmp-2 expression in the face, but downregulate cFHF-4 in the frontonasal process.
Copyright 2001 Wiley-Liss, Inc.
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11 MeSH Terms
Production and characterization of monoclonal antibodies to ARVCF.
Mariner DJ, Sirotkin H, Daniel JM, Lindman BR, Mernaugh RL, Patten AK, Thoreson MA, Reynolds AB
(1999) Hybridoma 18: 343-9
MeSH Terms: Abnormalities, Multiple, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibody Affinity, Antibody Formation, Armadillos, Binding Sites, Blotting, Western, Cadherins, Catenins, Cell Adhesion Molecules, Cell Line, Craniofacial Abnormalities, DiGeorge Syndrome, Dogs, Fluorescent Antibody Technique, Gene Deletion, Haplorhini, Heart Defects, Congenital, Humans, Hybridomas, Intercellular Junctions, Mice, Molecular Sequence Data, Phosphoproteins, Precipitin Tests, Rats, Repetitive Sequences, Amino Acid, Repetitive Sequences, Nucleic Acid, Sequence Homology, Amino Acid, Species Specificity, Velopharyngeal Insufficiency
Show Abstract · Added March 5, 2014
We have generated the first monoclonal antibodies (MAbs) to Armadillo repeat gene deleted in velo-cardiofacial syndrome (ARVCF), a recently identified Armadillo repeat-containing protein closely related to the catenin p120ctn. Six ARVCF-specific MAbs were characterized for isotype, species cross-reactivity, and utility in assays including immunofluorescence, immunoprecipitation, and Western blotting. All six antibodies were isotyped as IgG1 and several cross-reacted with ARVCF from a variety of species including human, rat, dog, and monkey, but not mouse. Importantly, none of the ARVCF MAbs cross-reacted with p120ctn, despite the high homology between these proteins. MAbs 3B2 and 4B1 were consistently the best in all applications and will provide valuable tools for further study of the role of ARVCF in cells.
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33 MeSH Terms
The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo.
Winnier GE, Hargett L, Hogan BL
(1997) Genes Dev 11: 926-40
MeSH Terms: Animals, Body Patterning, Cell Differentiation, Cell Division, Cell Lineage, Cell Movement, Craniofacial Abnormalities, DNA-Binding Proteins, Epithelium, Fetal Death, Forkhead Transcription Factors, Genes, Lethal, Homozygote, Mesoderm, Mice, Mice, Mutant Strains, Models, Biological, RNA, Messenger, Somites, Spine, Stem Cells, Tissue Distribution, Transcription Factors
Show Abstract · Added April 14, 2010
The gene mfh1, encoding a winged helix/forkhead domain transcription factor, is expressed in a dynamic pattern in paraxial and presomitic mesoderm and developing somites during mouse embryogenesis. Expression later becomes restricted to condensing mesenchyme of the vertebrae, head, limbs, and kidney. A targeted disruption of the gene was generated by homologous recombination in embryonic stem cells. Most homozygous mfh1 null embryos die prenatally but some survive to birth, with multiple craniofacial and vertebral column defects. Using molecular markers, we show that the initial formation and patterning of somites occurs normally in mutants. Differentiation of sclerotome-derived cells also appears unaffected, although a reduction of the level of some markers [e.g., mtwist, mf1, scleraxis, and alpha1(II) collagen] is seen in the anterior of homozygous mutants. The most significant difference, however, is a marked reduction in the proliferation of sclerotome-derived cells, as judged by BrdU incorporation. This proliferation defect was also seen in micromass cultures of somite-derived cells treated with transforming growth factor beta1 and fibroblast growth factors. Our findings establish a requirement for a winged helix/forkhead domain transcription factor in the development of the paraxial mesoderm. A model is proposed for the role of mfh1 in regulating the proliferation and differentiation of cell lineages giving rise to the axial skeleton and skull.
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23 MeSH Terms