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Article ; Online: Proper ciliary assembly is critical for restricting Hedgehog signaling during early eye development in mice.

Burnett, Jacob B / Lupu, Floria I / Eggenschwiler, Jonathan T

2017 Volume 430, Issue 1, Page(s) 32–40

Abstract: Patterning of the vertebrate eye into optic stalk, retinal pigment epithelium (RPE) and neural retina (NR) territories relies on a number of signaling pathways, but how these signals are interpreted by optic progenitors is not well understood. The ... ...

Abstract	Patterning of the vertebrate eye into optic stalk, retinal pigment epithelium (RPE) and neural retina (NR) territories relies on a number of signaling pathways, but how these signals are interpreted by optic progenitors is not well understood. The primary cilium is a microtubule-based organelle that is essential for Hedgehog (Hh) signaling, but it has also been implicated in the regulation of other signaling pathways. Here, we show that the optic primordium is ciliated during early eye development and that ciliogenesis is essential for proper patterning and morphogenesis of the mouse eye. Ift172 mutants fail to generate primary cilia and exhibit patterning defects that resemble those of Gli3 mutants, suggesting that cilia are required to restrict Hh activity during eye formation. Ift122 mutants, which produce cilia with abnormal morphology, generate optic vesicles that fail to invaginate to produce the optic cup. These mutants also lack formation of the lens, RPE and NR. Such phenotypic features are accompanied by strong, ectopic Hh pathway activity, evidenced by altered gene expression patterns. Removal of GLI2 from Ift122 mutants rescued several aspects of optic cup and lens morphogenesis as well as RPE and NR specification. Collectively, our data suggest that proper assembly of primary cilia is critical for restricting the Hedgehog pathway during eye formation in the mouse.
MeSH term(s)	Animals ; Body Patterning ; Cilia/metabolism ; Eye/embryology ; Eye/metabolism ; Hedgehog Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Kruppel-Like Transcription Factors/metabolism ; Lens, Crystalline/cytology ; Lens, Crystalline/metabolism ; Mice ; Models, Biological ; Morphogenesis ; Mutation/genetics ; Signal Transduction ; Stem Cells/cytology ; Stem Cells/metabolism ; Zinc Finger Protein Gli2
Chemical Substances	Gli2 protein, mouse ; Hedgehog Proteins ; Ift122 protein, mouse ; Ift172 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Kruppel-Like Transcription Factors ; Zinc Finger Protein Gli2
Language	English
Publishing date	2017-08-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2017.07.012
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Article ; Online: Cell cycle-related kinase regulates mammalian eye development through positive and negative regulation of the Hedgehog pathway.

Lupu, Floria I / Burnett, Jacob B / Eggenschwiler, Jonathan T

Developmental biology

2017 Volume 434, Issue 1, Page(s) 24–35

Abstract: Cell cycle-related kinase (CCRK) is a conserved regulator of ciliogenesis whose loss in mice leads to a wide range of developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, and microphthalmia. Here, we investigate the ...

Abstract	Cell cycle-related kinase (CCRK) is a conserved regulator of ciliogenesis whose loss in mice leads to a wide range of developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, and microphthalmia. Here, we investigate the role of CCRK in mouse eye development. Ccrk mutants show dramatic patterning defects, with an expansion of the optic stalk domain into the optic cup, as well as an expansion of the retinal pigment epithelium (RPE) into neural retina (NR) territory. In addition, Ccrk mutants display a shortened optic stalk. These defects are associated with bimodal changes in Hedgehog (Hh) pathway activity within the eye, including the loss of proximal, high level responses but a gain in distal, low level responses. We simultaneously removed the Hh activator GLI2 in Ccrk mutants (Ccrk-/-;Gli2-/-), which resulted in rescue of optic cup patterning and exacerbation of optic stalk length defects. Next, we disrupted the Hh pathway antagonist GLI3 in mutants lacking CCRK (Ccrk-/-;Gli3-/-), which lead to even greater expansion of the RPE markers into the NR domain and a complete loss of NR specification within the optic cup. These results indicate that CCRK functions in eye development by both positively and negatively regulating the Hh pathway, and they reveal distinct requirements for Hh signaling in patterning and morphogenesis of the eyes.
MeSH term(s)	Animals ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Embryo, Mammalian/cytology ; Embryo, Mammalian/embryology ; Eye/cytology ; Eye/embryology ; Female ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Male ; Mice ; Mice, Mutant Strains ; Organogenesis/physiology ; Signal Transduction/physiology ; Zinc Finger Protein Gli2/genetics ; Zinc Finger Protein Gli2/metabolism
Chemical Substances	Gli2 protein, mouse ; Hedgehog Proteins ; Zinc Finger Protein Gli2 ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; cyclin-dependent kinase-activating kinase (EC 2.7.11.22)
Language	English
Publishing date	2017-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2017.10.022
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Article: Cilia and developmental signaling.

Eggenschwiler, Jonathan T / Anderson, Kathryn V

Annual review of cell and developmental biology

2007 Volume 23, Page(s) 345–373

Abstract: Recent studies have revealed unexpected connections between the mammalian Hedgehog (Hh) signal transduction pathway and the primary cilium, a microtubule-based organelle that protrudes from the surface of most vertebrate cells. Intraflagellar transport ... ...

Abstract	Recent studies have revealed unexpected connections between the mammalian Hedgehog (Hh) signal transduction pathway and the primary cilium, a microtubule-based organelle that protrudes from the surface of most vertebrate cells. Intraflagellar transport proteins, which are required for the construction of cilia, are essential for all responses to mammalian Hh proteins, and proteins required for Hh signal transduction are enriched in primary cilia. The phenotypes of different mouse mutants that affect ciliary proteins suggest that cilia may act as processive machines that organize sequential steps in the Hh signal transduction pathway. Cilia on vertebrate cells are likely to be important in additional developmental signaling pathways and are required for PDGF receptor alpha signaling in cultured fibroblasts. Cilia are not essential for either canonical or noncanonical Wnt signaling, although cell-type-specific modulation of cilia components may link cilia and Wnt signaling in some tissues. Because ciliogenesis in invertebrates is limited to a very small number of specialized cell types, the role of cilia in developmental signaling pathways is likely a uniquely vertebrate phenomenon.
MeSH term(s)	Animals ; Body Patterning ; Cilia/physiology ; Genetic Diseases, Inborn/metabolism ; Hedgehog Proteins/metabolism ; Humans ; Mice ; Neural Tube/growth & development ; Protein Transport/genetics ; Signal Transduction
Chemical Substances	Hedgehog Proteins
Language	English
Publishing date	2007
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1293750-2
ISSN	1530-8995 ; 1081-0706
ISSN (online)	1530-8995
ISSN	1081-0706
DOI	10.1146/annurev.cellbio.23.090506.123249
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Article ; Online: Evolution of a chordate-specific mechanism for myoblast fusion.

Zhang, Haifeng / Shang, Renjie / Kim, Kwantae / Zheng, Wei / Johnson, Christopher J / Sun, Lei / Niu, Xiang / Liu, Liang / Zhou, Jingqi / Liu, Lingshu / Zhang, Zheng / Uyeno, Theodore A / Pei, Jimin / Fissette, Skye D / Green, Stephen A / Samudra, Sukhada P / Wen, Junfei / Zhang, Jianli / Eggenschwiler, Jonathan T /

Menke, Douglas B / Bronner, Marianne E / Grishin, Nick V / Li, Weiming / Ye, Kaixiong / Zhang, Yang / Stolfi, Alberto / Bi, Pengpeng

Science advances

2022 Volume 8, Issue 35, Page(s) eadd2696

Abstract: Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane- ... ...

Abstract	Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here, we report that
Language	English
Publishing date	2022-09-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.add2696
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Article: Cell cycle-related kinase regulates mammalian eye development through positive and negative regulation of the Hedgehog pathway

Lupu, Floria I / Burnett, Jacob B / Eggenschwiler, Jonathan T

Developmental biology. 2017,

2017

Abstract	Cell cycle-related kinase (CCRK) is a conserved regulator of ciliogenesis whose loss in mice leads to a wide range of developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, and microphthalmia. Here, we investigate the role of CCRK in mouse eye development. Ccrk mutants show dramatic patterning defects, with an expansion of the optic stalk domain into the optic cup, as well as an expansion of the retinal pigment epithelium (RPE) into neural retina (NR) territory. In addition, Ccrk mutants display a shortened optic stalk. These defects are associated with bimodal changes in Hedgehog (Hh) pathway activity within the eye, including the loss of proximal, high level responses but a gain in distal, low level responses. We simultaneously removed the Hh activator GLI2 in Ccrk mutants (Ccrk-/-;Gli2-/-), which resulted in rescue of optic cup patterning and exacerbation of optic stalk length defects. Next, we disrupted the Hh pathway antagonist GLI3 in mutants lacking CCRK (Ccrk-/-;Gli3-/-) which lead to even greater expansion of the RPE markers into the NR domain and a complete loss of NR specification within the optic cup. These results indicate that CCRK functions in eye development by both positively and negatively regulating the Hh pathway, and they reveal distinct requirements for Hh signaling in patterning and morphogenesis of the eyes.
Keywords	antagonists ; epithelium ; mice ; morphogenesis ; mutants ; retina
Language	English
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2017.10.022
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Article: Proper ciliary assembly is critical for restricting Hedgehog signaling during early eye development in mice

Burnett, Jacob B / Lupu, Floria I / Eggenschwiler, Jonathan T

Developmental biology. 2017,

2017

Abstract	Patterning of the vertebrate eye into optic stalk, retinal pigment epithelium (RPE) and neural retina (NR) territories relies on a number of signaling pathways, but how these signals are interpreted by optic progenitors is not well understood. The primary cilium is a microtubule-based organelle that is essential for Hedgehog (Hh) signaling, but it has also been implicated in the regulation of other signaling pathways. Here, we show that the optic primordium is ciliated during early eye development and that ciliogenesis is essential for proper patterning and morphogenesis of the mouse eye. Ift172 mutants fail to generate primary cilia and exhibit patterning defects that resemble those of Gli3 mutants, suggesting that cilia are required to restrict Hh activity during eye formation. Ift122 mutants, which produce cilia with abnormal morphology, generate optic vesicles that fail to invaginate to produce the optic cup. These mutants also lack formation of the lens, RPE and NR. Such phenotypic features are accompanied by strong, ectopic Hh pathway activity, evidenced by altered gene expression patterns. Removal of GLI2 from Ift122 mutants rescued several aspects of optic cup and lens morphogenesis as well as RPE and NR specification. Collectively, our data suggest that proper assembly of primary cilia is critical for restricting the Hedgehog pathway during eye formation in the mouse.
Keywords	cilia ; epithelium ; gene expression regulation ; mice ; morphogenesis ; mutants ; phenotype ; retina ; signal transduction
Language	English
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2017.07.012
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A selectable all-in-one CRISPR prime editing piggyBac transposon allows for highly efficient gene editing in human cell lines.

Eggenschwiler, Reto / Gschwendtberger, Thomas / Felski, Christian / Jahn, Christopher / Langer, Florian / Sterneckert, Jared / Hermann, Andreas / Lühmann, Jonathan / Steinemann, Doris / Haase, Alexandra / Martin, Ulrich / Petri, Susanne / Cantz, Tobias

Scientific reports

2021 Volume 11, Issue 1, Page(s) 22154

Abstract: CRISPR prime-editors are emergent tools for genome editing and offer a versatile alternative approach to HDR-based genome engineering or DNA base-editors. However, sufficient prime-editor expression levels and availability of optimized transfection ... ...

Abstract	CRISPR prime-editors are emergent tools for genome editing and offer a versatile alternative approach to HDR-based genome engineering or DNA base-editors. However, sufficient prime-editor expression levels and availability of optimized transfection protocols may affect editing efficiencies, especially in hard-to-transfect cells like hiPSC. Here, we show that piggyBac prime-editing (PB-PE) allows for sustained expression of prime-editors. We demonstrate proof-of-concept for PB-PE in a newly designed lentiviral traffic light reporter, which allows for estimation of gene correction and defective editing resulting in indels, based on expression of two different fluorophores. PB-PE can prime-edit more than 50% of hiPSC cells after antibiotic selection. We also show that improper design of pegRNA cannot simply be overcome by extended expression, but PB-PE allows for estimation of effectiveness of selected pegRNAs after few days of cultivation time. Finally, we implemented PB-PE for efficient editing of an amyotrophic lateral sclerosis-associated mutation in the SOD1-gene of patient-derived hiPSC. Progress of genome editing can be monitored by Sanger-sequencing, whereas PB-PE vectors can be removed after editing and excised cells can be enriched by fialuridine selection. Together, we present an efficient prime-editing toolbox, which can be robustly used in a variety of cell lines even when non-optimized transfection-protocols are applied.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; CRISPR-Cas Systems ; Cell Line ; Gene Editing/methods ; HEK293 Cells ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mutation ; Superoxide Dismutase-1/genetics ; Transfection/methods
Chemical Substances	Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2021-11-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-01689-2
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Article ; Online: Rab23 regulates Nodal signaling in vertebrate left-right patterning independently of the Hedgehog pathway.

Fuller, Kimberly / O'Connell, Joyce T / Gordon, Julie / Mauti, Olivier / Eggenschwiler, Jonathan

Developmental biology

2014 Volume 391, Issue 2, Page(s) 182–195

Abstract: Asymmetric fluid flow in the node and Nodal signaling in the left lateral plate mesoderm (LPM) drive left-right patterning of the mammalian body plan. However, the mechanisms linking fluid flow to asymmetric gene expression in the LPM remain unclear. ... ...

Abstract	Asymmetric fluid flow in the node and Nodal signaling in the left lateral plate mesoderm (LPM) drive left-right patterning of the mammalian body plan. However, the mechanisms linking fluid flow to asymmetric gene expression in the LPM remain unclear. Here we show that the small GTPase Rab23, known for its role in Hedgehog signaling, plays a separate role in Nodal signaling and left-right patterning in the mouse embryo. Rab23 is not required for initial symmetry breaking in the node, but it is required for expression of Nodal and Nodal target genes in the LPM. Microinjection of Nodal protein and transfection of Nodal cDNA in the embryo indicate that Rab23 is required for the production of functional Nodal signals, rather than the response to them. Using gain- and loss-of function approaches, we show that Rab23 plays a similar role in zebrafish, where it is required in the teleost equivalent of the mouse node, Kupffer׳s vesicle. Collectively, these data suggest that Rab23 is an essential component of the mechanism that transmits asymmetric patterning information from the node to the LPM.
MeSH term(s)	Animals ; Body Patterning/genetics ; Embryo Culture Techniques ; Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Growth Differentiation Factor 1/biosynthesis ; Growth Differentiation Factor 1/genetics ; Hedgehog Proteins/metabolism ; Kinesin/genetics ; Kruppel-Like Transcription Factors/genetics ; Mesoderm/embryology ; Mice ; Mice, Inbred C3H ; Mice, Transgenic ; Morpholinos/genetics ; Nodal Protein/genetics ; Nodal Protein/metabolism ; Signal Transduction ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism ; Zinc Finger Protein Gli2 ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Gli2 protein, mouse ; Growth Differentiation Factor 1 ; Hedgehog Proteins ; Kif3a protein, mouse ; Kruppel-Like Transcription Factors ; Morpholinos ; Nodal Protein ; Nodal protein, mouse ; Zebrafish Proteins ; Zinc Finger Protein Gli2 ; Rab23 protein, mouse (EC 3.6.1.-) ; Rab23 protein, zebrafish (EC 3.6.1.-) ; Kinesin (EC 3.6.4.4) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2014-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2014.04.012
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Article: Analysis of hedgehog signaling in mouse intraflagellar transport mutants.

Ko, Hyuk W / Liu, Aimin / Eggenschwiler, Jonathan T

Methods in cell biology

2009 Volume 93, Page(s) 347–369

Abstract: Intraflagellar transport (IFT) has been studied for decades in model systems such as Chlamydomonas and Caenorhabditis elegans. More recently, IFT has been investigated using genetic approaches in mammals using the mouse as a model system. Through such ... ...

Abstract	Intraflagellar transport (IFT) has been studied for decades in model systems such as Chlamydomonas and Caenorhabditis elegans. More recently, IFT has been investigated using genetic approaches in mammals using the mouse as a model system. Through such studies, a new appreciation of the importance of IFT and cilia in mammalian signal transduction has emerged. Specifically, IFT has been shown to play a key role in controlling signaling by Sonic and Indian Hedgehog (Hh) ligands. The effects of mutations in IFT components on Sonic Hh signaling in the embryo are complex and differ depending on the nature of the components, alleles, and tissues examined. For this reason, we provide a basis for analyzing the phenotype as a guide for those investigators who study IFT in cell culture or use invertebrate systems and wish to extend their studies to include development of the mouse embryo. We provide an overview of Sonic Hh-dependent tissue patterning in the developing neural tube and limb buds, the two systems in which it has been studied most extensively, and we show examples of how this patterning is disrupted by mutations in mouse IFT components.
MeSH term(s)	Animals ; Biological Transport/genetics ; Biological Transport/physiology ; Body Patterning/physiology ; Cilia/metabolism ; Cilia/ultrastructure ; Embryo, Mammalian/anatomy & histology ; Embryo, Mammalian/physiology ; Flagella/metabolism ; Flagella/ultrastructure ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Immunohistochemistry/instrumentation ; Immunohistochemistry/methods ; In Situ Hybridization/instrumentation ; In Situ Hybridization/methods ; Mice ; Mutation ; Signal Transduction/physiology
Chemical Substances	Hedgehog Proteins
Language	English
Publishing date	2009-12-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	0091-679X
ISSN	0091-679X
DOI	10.1016/S0091-679X(08)93017-X
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Article ; Online: Complex interactions between genes controlling trafficking in primary cilia.

Ocbina, Polloneal Jymmiel R / Eggenschwiler, Jonathan T / Moskowitz, Ivan / Anderson, Kathryn V

Nature genetics

2011 Volume 43, Issue 6, Page(s) 547–553

Abstract: Cilia-associated human genetic disorders are striking in the diversity of their abnormalities and their complex inheritance. Inactivation of the retrograde ciliary motor by mutations in DYNC2H1 causes skeletal dysplasias that have strongly variable ... ...

Abstract	Cilia-associated human genetic disorders are striking in the diversity of their abnormalities and their complex inheritance. Inactivation of the retrograde ciliary motor by mutations in DYNC2H1 causes skeletal dysplasias that have strongly variable expressivity. Here we define previously unknown genetic relationships between Dync2h1 and other genes required for ciliary trafficking. Mutations in mouse Dync2h1 disrupt cilia structure, block Sonic hedgehog signaling and cause midgestation lethality. Heterozygosity for Ift172, a gene required for anterograde ciliary trafficking, suppresses cilia phenotypes, Sonic hedgehog signaling defects and early lethality of Dync2h1 homozygotes. Ift122, like Dync2h1, is required for retrograde ciliary trafficking, but reduction of Ift122 gene dosage also suppresses the Dync2h1 phenotype. These genetic interactions illustrate the cell biology underlying ciliopathies and argue that mutations in intraflagellar transport genes cause their phenotypes because of their roles in cilia architecture rather than direct roles in signaling.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Carrier Proteins/metabolism ; Cilia/genetics ; Cytoplasmic Dyneins/genetics ; Cytoskeletal Proteins ; Fibroblasts/metabolism ; Hedgehog Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/physiology ; Mice ; Mutation
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Cytoskeletal Proteins ; DYNC2H1 protein, human ; Hedgehog Proteins ; Ift122 protein, mouse ; Ift172 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Shh protein, mouse ; Cytoplasmic Dyneins (EC 3.6.4.2)
Language	English
Publishing date	2011-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/ng.832
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