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Article ; Online: Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse.

Bangs, Fiona K / Miller, Paul / O'Neill, Eric

2020 Volume 13, Issue 7

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas; however, in the presence of oncogenic KRAS, regeneration is blocked and ADM can give rise to PanIN lesions. Here, we used a 3D mouse acinar culture that recapitulates ADM
MeSH term(s)	Adenocarcinoma in Situ/genetics ; Adenocarcinoma in Situ/metabolism ; Adenocarcinoma in Situ/pathology ; Animals ; Aurora Kinase A/genetics ; Aurora Kinase A/metabolism ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Cell Culture Techniques ; Cells, Cultured ; Cilia/genetics ; Cilia/metabolism ; Cilia/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Genes, ras ; Hedgehog Proteins/metabolism ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Male ; Metaplasia ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Pancreatic Cyst/genetics ; Pancreatic Cyst/metabolism ; Pancreatic Cyst/pathology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Signal Transduction
Chemical Substances	Hedgehog Proteins ; Aurka protein, mouse (EC 2.7.11.1) ; Aurora Kinase A (EC 2.7.11.1) ; Hdac2 protein, mouse (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98)
Language	English
Publishing date	2020-07-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.044289
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Article ; Online: Primary Cilia and Mammalian Hedgehog Signaling.

Bangs, Fiona / Anderson, Kathryn V

Cold Spring Harbor perspectives in biology

2017 Volume 9, Issue 5

Abstract: It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the mouse that identified a set of genes that are required for both normal Hh signaling and ... ...

Abstract	It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the mouse that identified a set of genes that are required for both normal Hh signaling and for the formation of primary cilia. Since then, dozens of mouse mutations have been identified that disrupt cilia in a variety of ways and have complex effects on Hedgehog signaling. Here, we summarize the genetic and developmental studies used to deduce how Hedgehog signal transduction is linked to cilia and the complex effects that perturbation of cilia structure can have on Hh signaling. We conclude by describing the current status of our understanding of the cell-type-specific regulation of ciliogenesis and how that determines the ability of cells to respond to Hedgehog ligands.
MeSH term(s)	Animals ; Cilia/physiology ; Hedgehog Proteins/metabolism ; Mammals/physiology ; Signal Transduction
Chemical Substances	Hedgehog Proteins
Language	English
Publishing date	2017-05-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a028175
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Article ; Online: Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse

Fiona K. Bangs / Paul Miller / Eric O'Neill

Disease Models & Mechanisms, Vol 13, Iss

2020 Volume 7

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas; however, in the presence of oncogenic KRAS, regeneration is blocked and ADM can give rise to PanIN lesions. Here, we used a 3D mouse acinar culture that recapitulates ADM in vitro to explore how KRAS prevents regeneration. Regeneration is regulated by Hedgehog (Hh) signalling, which is transduced via the primary cilium. In wild-type acini, cilia assemble upon ADM and Hh target gene expression is upregulated; however, ciliogenesis and Hh signalling are suppressed during ADM in cells expressing oncogenic KRAS. We show that ciliogenesis fails due to ectopic activation of the cilium disassembly pathway, which is mediated by AurkA, a direct transcriptional target of KRAS. Inhibition of AurkA is able to rescue primary cilia and restore Hh signalling. We suggest that this could be used as a mechanism to prevent the formation of early lesions and thereby prevent progression to PDAC.
Keywords	acinar-ductal metaplasia ; hedgehog signalling ; kras ; pancreatic ductal adenocarcinoma ; primary cilia ; Medicine ; R ; Pathology ; RB1-214
Subject code	570
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
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Article ; Online: The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.

Goetz, Sarah C / Bangs, Fiona / Barrington, Chloe L / Katsanis, Nicholas / Anderson, Kathryn V

PloS one

2017 Volume 12, Issue 3, Page(s) e0173399

Abstract: The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ... ...

Abstract	The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ciliopathy-associated genes are components of a handful of multi-protein complexes important for the transport of cargo to the basal body and/or into the cilium. A key question is whether different complexes cooperate in cilia formation, and whether they participate in cilium assembly in conjunction with intraflagellar transport (IFT) proteins. To examine how ciliopathy protein complexes might function together, we have analyzed double mutants of an allele of the Meckel syndrome (MKS) complex protein MKS1 and the BBSome protein BBS4. We find that Mks1; Bbs4 double mutant mouse embryos exhibit exacerbated defects in Hedgehog (Hh) dependent patterning compared to either single mutant, and die by E14.5. Cells from double mutant embryos exhibit a defect in the trafficking of ARL13B, a ciliary membrane protein, resulting in disrupted ciliary structure and signaling. We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172. Despite each single mutant surviving until around birth, Mks1; Ift172avc1 double mutants die at mid-gestation, and exhibit a dramatic failure of cilia formation. We also find that Mks1 interacts genetically with an allele of Dync2h1, the IFT retrograde motor. Thus, we have demonstrated that the MKS transition zone complex cooperates with the BBSome to mediate trafficking of specific trans-membrane receptors to the cilium. Moreover, the genetic interaction of Mks1 with components of IFT machinery suggests that the transition zone complex facilitates IFT to promote cilium assembly and structure.
MeSH term(s)	Animals ; Biological Transport ; Cells, Cultured ; Ciliary Motility Disorders/metabolism ; Encephalocele/metabolism ; Flagella/metabolism ; Hedgehog Proteins/metabolism ; Mice ; Microscopy, Electron, Scanning ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/metabolism ; Polycystic Kidney Diseases/metabolism ; Protein Binding ; Proteins/metabolism ; Proteins/physiology ; Retinitis Pigmentosa
Chemical Substances	BBS4 protein, mouse ; Hedgehog Proteins ; MKS1 protein, mouse ; Microtubule-Associated Proteins ; Proteins
Language	English
Publishing date	2017-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0173399
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Article ; Online: Lineage specificity of primary cilia in the mouse embryo.

Bangs, Fiona K / Schrode, Nadine / Hadjantonakis, Anna-Katerina / Anderson, Kathryn V

Nature cell biology

2015 Volume 17, Issue 2, Page(s) 113–122

Abstract: Primary cilia are required for vertebrate cells to respond to specific intercellular signals. Here we define when and where primary cilia appear in the mouse embryo using a transgenic line that expresses ARL13B-mCherry in cilia and Centrin 2-GFP in ... ...

Abstract	Primary cilia are required for vertebrate cells to respond to specific intercellular signals. Here we define when and where primary cilia appear in the mouse embryo using a transgenic line that expresses ARL13B-mCherry in cilia and Centrin 2-GFP in centrosomes. Primary cilia first appear on cells of the epiblast at E6.0 and are subsequently present on all derivatives of the epiblast. In contrast, extraembryonic cells of the visceral endoderm and trophectoderm lineages have centrosomes but no cilia. Stem cell lines derived from embryonic lineages recapitulate the in vivo pattern: epiblast stem cells are ciliated, whereas trophoblast stem cells and extraembryonic endoderm (XEN) stem cells lack cilia. Basal bodies in XEN cells are mature and can form cilia when the AURKA-HDAC6 cilium disassembly pathway is inhibited. The lineage-dependent distribution of cilia is stable throughout much of gestation, defining which cells in the placenta and yolk sac are able to respond to Hedgehog ligands.
MeSH term(s)	ADP-Ribosylation Factors/metabolism ; Animals ; Basal Bodies/metabolism ; Cell Line ; Cell Lineage ; Chickens ; Cilia/metabolism ; Embryo Implantation ; Embryo, Mammalian/cytology ; Embryo, Mammalian/metabolism ; Endoderm/cytology ; Endoderm/metabolism ; Female ; Gastrulation ; Mice ; Pregnancy ; Yolk Sac/cytology ; Yolk Sac/metabolism
Chemical Substances	Arl13b protein, mouse ; ADP-Ribosylation Factors (EC 3.6.5.2)
Language	English
Publishing date	2015-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb3091
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Article ; Online: The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.

Sarah C Goetz / Fiona Bangs / Chloe L Barrington / Nicholas Katsanis / Kathryn V Anderson

PLoS ONE, Vol 12, Iss 3, p e

2017 Volume 0173399

Abstract	The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ciliopathy-associated genes are components of a handful of multi-protein complexes important for the transport of cargo to the basal body and/or into the cilium. A key question is whether different complexes cooperate in cilia formation, and whether they participate in cilium assembly in conjunction with intraflagellar transport (IFT) proteins. To examine how ciliopathy protein complexes might function together, we have analyzed double mutants of an allele of the Meckel syndrome (MKS) complex protein MKS1 and the BBSome protein BBS4. We find that Mks1; Bbs4 double mutant mouse embryos exhibit exacerbated defects in Hedgehog (Hh) dependent patterning compared to either single mutant, and die by E14.5. Cells from double mutant embryos exhibit a defect in the trafficking of ARL13B, a ciliary membrane protein, resulting in disrupted ciliary structure and signaling. We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172. Despite each single mutant surviving until around birth, Mks1; Ift172avc1 double mutants die at mid-gestation, and exhibit a dramatic failure of cilia formation. We also find that Mks1 interacts genetically with an allele of Dync2h1, the IFT retrograde motor. Thus, we have demonstrated that the MKS transition zone complex cooperates with the BBSome to mediate trafficking of specific trans-membrane receptors to the cilium. Moreover, the genetic interaction of Mks1 with components of IFT machinery suggests that the transition zone complex facilitates IFT to promote cilium assembly and structure.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment.

He, Mu / Subramanian, Radhika / Bangs, Fiona / Omelchenko, Tatiana / Liem, Karel F / Kapoor, Tarun M / Anderson, Kathryn V

Nature cell biology

2014 Volume 16, Issue 7, Page(s) 663–672

Abstract: Mammalian Hedgehog (Hh) signal transduction requires a primary cilium, a microtubule-based organelle, and the Gli-Sufu complexes that mediate Hh signalling, which are enriched at cilia tips. Kif7, a kinesin-4 family protein, is a conserved regulator of ... ...

Abstract	Mammalian Hedgehog (Hh) signal transduction requires a primary cilium, a microtubule-based organelle, and the Gli-Sufu complexes that mediate Hh signalling, which are enriched at cilia tips. Kif7, a kinesin-4 family protein, is a conserved regulator of the Hh signalling pathway and a human ciliopathy protein. Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. Kif7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. Instead, a central function of Kif7 in the mammalian Hh pathway is to control cilium architecture and to create a single cilium tip compartment, where Gli-Sufu activity can be correctly regulated.
MeSH term(s)	Animals ; Axoneme/genetics ; Axoneme/metabolism ; Cell Line ; Cells, Cultured ; Cilia/chemistry ; Cilia/metabolism ; Fibroblasts/metabolism ; HEK293 Cells ; Hedgehog Proteins/metabolism ; Humans ; Kinesins/genetics ; Kinesins/metabolism ; Mice ; Microtubules/metabolism ; Mutation ; NIH 3T3 Cells ; Protein Binding ; Protein Transport ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Signal Transduction
Chemical Substances	Hedgehog Proteins ; Recombinant Proteins ; Kif7 protein, mouse (EC 3.6.1.-) ; Kinesins (EC 3.6.4.4)
Language	English
Publishing date	2014-06-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb2988
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Article ; Online: Enhancer elements upstream of the SHOX gene are active in the developing limb.

Durand, Claudia / Bangs, Fiona / Signolet, Jason / Decker, Eva / Tickle, Cheryll / Rappold, Gudrun

European journal of human genetics : EJHG

2009 Volume 18, Issue 5, Page(s) 527–532

Abstract: Léri-Weill Dyschondrosteosis (LWD) is a dominant skeletal disorder characterized by short stature and distinct bone anomalies. SHOX gene mutations and deletions of regulatory elements downstream of SHOX resulting in haploinsufficiency have been found in ... ...

Abstract	Léri-Weill Dyschondrosteosis (LWD) is a dominant skeletal disorder characterized by short stature and distinct bone anomalies. SHOX gene mutations and deletions of regulatory elements downstream of SHOX resulting in haploinsufficiency have been found in patients with LWD. SHOX encodes a homeodomain transcription factor and is known to be expressed in the developing limb. We have now analyzed the regulatory significance of the region upstream of the SHOX gene. By comparative genomic analyses, we identified several conserved non-coding elements, which subsequently were tested in an in ovo enhancer assay in both chicken limb bud and cornea, where SHOX is also expressed. In this assay, we found three enhancers to be active in the developing chicken limb, but none were functional in the developing cornea. A screening of 60 LWD patients with an intact SHOX coding and downstream region did not yield any deletion of the upstream enhancer region. Thus, we speculate that SHOX upstream deletions occur at a lower frequency because of the structural organization of this genomic region and/or that SHOX upstream deletions may cause a phenotype that differs from the one observed in LWD.
MeSH term(s)	Animals ; Chick Embryo ; Chickens/genetics ; Chromosomes, Human, X/genetics ; Conserved Sequence/genetics ; DNA, Intergenic/genetics ; Enhancer Elements, Genetic/genetics ; Extremities/embryology ; Genetic Testing ; Genome, Human/genetics ; Homeodomain Proteins/genetics ; Humans ; Sequence Homology, Nucleic Acid ; Short Stature Homeobox Protein ; Telomere/genetics
Chemical Substances	DNA, Intergenic ; Homeodomain Proteins ; SHOX protein, human ; Short Stature Homeobox Protein
Language	English
Publishing date	2009-12-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/ejhg.2009.216
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Article ; Online: 3D expression patterns of cell cycle genes in the developing chick wing and comparison with expression patterns of genes implicated in digit specification.

Welten, Monique / Pavlovska, Gordana / Chen, Yu / Teruoka, Yuko / Fisher, Malcolm / Bangs, Fiona / Towers, Matthew / Tickle, Cheryll

Developmental dynamics : an official publication of the American Association of Anatomists

2011 Volume 240, Issue 5, Page(s) 1278–1288

Abstract: Sonic hedgehog (Shh) signalling controls integrated specification of digit pattern and growth in the chick wing but downstream gene networks remain to be unravelled. We analysed 3D expression patterns of genes encoding cell cycle regulators using Optical ...

Abstract	Sonic hedgehog (Shh) signalling controls integrated specification of digit pattern and growth in the chick wing but downstream gene networks remain to be unravelled. We analysed 3D expression patterns of genes encoding cell cycle regulators using Optical Projection Tomography. Hierarchical clustering of spatial matrices of gene expression revealed a dorsal layer of the wing bud, in which almost all genes were expressed, and that genes encoding positive cell cycle regulators had similar expression patterns while those of N-myc and CyclinD2 were distinct but closely related. We compared these patterns computationally with those of genes implicated in digit specification and Ptch1, 50 genes in total. Nineteen genes have similar posterior expression to Ptch1, including Hoxd13, Sall1, Hoxd11, and Bmp2, all likely Gli targets in mouse limb, and cell cycle genes, N-myc, CyclinD2. We suggest that these genes contribute to a network integrating digit specification and growth in response to Shh.
MeSH term(s)	Animals ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/metabolism ; Chick Embryo ; Chickens ; Extremities/embryology ; Extremities/physiology ; Gene Expression Regulation, Developmental/genetics ; Gene Expression Regulation, Developmental/physiology ; Genes, cdc/physiology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Wings, Animal/embryology ; Wings, Animal/metabolism
Chemical Substances	Bone Morphogenetic Protein 2 ; Homeodomain Proteins ; Transcription Factors
Language	English
Publishing date	2011-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.22633
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Article ; Online: Generation of mice with functional inactivation of talpid3, a gene first identified in chicken.

Bangs, Fiona / Antonio, Nicole / Thongnuek, Peerapat / Welten, Monique / Davey, Megan G / Briscoe, James / Tickle, Cheryll

Development (Cambridge, England)

2011 Volume 138, Issue 15, Page(s) 3261–3272

Abstract: Specification of digit number and identity is central to digit pattern in vertebrate limbs. The classical talpid(3) chicken mutant has many unpatterned digits together with defects in other regions, depending on hedgehog (Hh) signalling, and exhibits ... ...

Abstract	Specification of digit number and identity is central to digit pattern in vertebrate limbs. The classical talpid(3) chicken mutant has many unpatterned digits together with defects in other regions, depending on hedgehog (Hh) signalling, and exhibits embryonic lethality. The talpid(3) chicken has a mutation in KIAA0586, which encodes a centrosomal protein required for the formation of primary cilia, which are sites of vertebrate Hh signalling. The highly conserved exons 11 and 12 of KIAA0586 are essential to rescue cilia in talpid(3) chicken mutants. We constitutively deleted these two exons to make a talpid3(-/-) mouse. Mutant mouse embryos lack primary cilia and, like talpid(3) chicken embryos, have face and neural tube defects but also defects in left/right asymmetry. Conditional deletion in mouse limb mesenchyme results in polydactyly and in brachydactyly and a failure of subperisoteal bone formation, defects that are attributable to abnormal sonic hedgehog and Indian hedgehog signalling, respectively. Like talpid(3) chicken limbs, the mutant mouse limbs are syndactylous with uneven digit spacing as reflected in altered Raldh2 expression, which is normally associated with interdigital mesenchyme. Both mouse and chicken mutant limb buds are broad and short. talpid3(-/-) mouse cells migrate more slowly than wild-type mouse cells, a change in cell behaviour that possibly contributes to altered limb bud morphogenesis. This genetic mouse model will facilitate further conditional approaches, epistatic experiments and open up investigation into the function of the novel talpid3 gene using the many resources available for mice.
MeSH term(s)	Animals ; Chick Embryo ; Chickens/genetics ; Cilia/metabolism ; Embryo, Mammalian/abnormalities ; Embryo, Mammalian/anatomy & histology ; Embryo, Mammalian/physiology ; Female ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Limb Buds/abnormalities ; Limb Buds/anatomy & histology ; Limb Buds/embryology ; Limb Buds/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Morphogenesis/genetics ; Osteogenesis/physiology ; Proteins/genetics ; Proteins/metabolism ; Signal Transduction/physiology
Chemical Substances	Hedgehog Proteins ; Proteins ; Shh protein, mouse
Language	English
Publishing date	2011-05-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.063602
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