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Article: Non-coding RNAs: An Introduction.

Yang, Jennifer X / Rastetter, Raphael H / Wilhelm, Dagmar

Advances in experimental medicine and biology

2016 Volume 886, Page(s) 13–32

Abstract: For many years the main role of RNA, it addition to the housekeeping functions of for example tRNAs and rRNAs, was believed to be a messenger between the genes encoded on the DNA and the functional units of the cell, the proteins. This changed ... ...

Abstract	For many years the main role of RNA, it addition to the housekeeping functions of for example tRNAs and rRNAs, was believed to be a messenger between the genes encoded on the DNA and the functional units of the cell, the proteins. This changed drastically with the identification of the first small non-coding RNA, termed microRNA, some 20 years ago. This discovery opened the field of regulatory RNAs with no or little protein-coding potential. Since then many new classes of regulatory non-coding RNAs, including endogenous small interfering RNAs (endo-siRNAs), PIWI-associated RNAs (piRNAs), and long non-coding RNAs, have been identified and we have made amazing progress in elucidating their expression, biogenesis, mechanisms and mode of action, and function in many, if not all, biological processes. In this chapter we provide an introduction about the current knowledge of the main classes of non-coding RNAs, what is know about their biogenesis and mechanism of function.
MeSH term(s)	Animals ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism
Chemical Substances	MicroRNAs ; RNA, Small Interfering
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-94-017-7417-8_2
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Article ; Online: The role of non-coding RNAs in male sex determination and differentiation.

Rastetter, Raphael H / Smith, Craig A / Wilhelm, Dagmar

Reproduction (Cambridge, England)

2015 Volume 150, Issue 3, Page(s) R93–107

Abstract: A complex network of gene regulation and interaction drives male sex determination and differentiation. While many important protein-coding genes that are necessary for proper male development have been identified, many disorders in human sex development ...

Abstract	A complex network of gene regulation and interaction drives male sex determination and differentiation. While many important protein-coding genes that are necessary for proper male development have been identified, many disorders in human sex development are still unexplained at the molecular level. This suggests that key factors and regulatory mechanisms are still unknown. In recent years, extensive data have shown that different classes of non-coding RNAs (ncRNAs) play a role in almost all developmental and physiological pathways. Here we review what is known about their role in male sex determination and differentiation not only in mammals, but also other species. While for some processes a key role for ncRNA has been identified, we are still far from having a complete picture.
MeSH term(s)	Animals ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Genes, sry ; Humans ; Male ; Morphogenesis ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism ; SOX9 Transcription Factor/genetics ; SOX9 Transcription Factor/metabolism ; Sex Determination Processes/genetics ; Spermatogenesis/genetics ; Spermatozoa/metabolism ; Testis/embryology ; Testis/metabolism ; Y Chromosome
Chemical Substances	RNA, Long Noncoding ; RNA, Small Interfering ; RNA, Untranslated ; SOX9 Transcription Factor
Language	English
Publishing date	2015-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2034501-X
ISSN	1741-7899 ; 1470-1626 ; 1476-3990
ISSN (online)	1741-7899
ISSN	1470-1626 ; 1476-3990
DOI	10.1530/REP-15-0106
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Article ; Online: Coronin 1C-free primary mouse fibroblasts exhibit robust rearrangements in the orientation of actin filaments, microtubules and intermediate filaments.

Behrens, Juliane / Solga, Roxana / Ziemann, Anja / Rastetter, Raphael H / Berwanger, Carolin / Herrmann, Harald / Noegel, Angelika A / Clemen, Christoph S

European journal of cell biology

2016 Volume 95, Issue 8, Page(s) 239–251

Abstract: Coronin 1C is an established modulator of actin cytoskeleton dynamics. It has been shown to be involved in protrusion formation, cell migration and invasion. Here, we report the generation of primary fibroblasts from coronin 1C knock-out mice in order to ...

Abstract	Coronin 1C is an established modulator of actin cytoskeleton dynamics. It has been shown to be involved in protrusion formation, cell migration and invasion. Here, we report the generation of primary fibroblasts from coronin 1C knock-out mice in order to investigate the impact of the loss of coronin 1C on cellular structural organisation. We demonstrate that the lack of coronin 1C not only affects the actin system, but also the microtubule and the vimentin intermediate filament networks. In particular, we show that the knock-out cells exhibit a reduced proliferation rate, impaired cell migration and protrusion formation as well as an aberrant subcellular localisation and function of mitochondria. Moreover, we demonstrate that coronin 1C specifically interacts with the non-α-helical amino-terminal domain ("head") of vimentin. Our data suggest that coronin 1C acts as a cytoskeletal integrator of actin filaments, microtubules and intermediate filaments.
MeSH term(s)	4-Butyrolactone/analogs & derivatives ; 4-Butyrolactone/metabolism ; Actin Cytoskeleton/metabolism ; Animals ; Cell Movement ; Fibroblasts/metabolism ; Intermediate Filaments ; Mice ; Mice, Knockout ; Microtubules/metabolism
Chemical Substances	coronin ; 4-Butyrolactone (OL659KIY4X)
Language	English
Publishing date	2016-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	391967-5
ISSN	1618-1298 ; 0070-2463 ; 0171-9335
ISSN (online)	1618-1298
ISSN	0070-2463 ; 0171-9335
DOI	10.1016/j.ejcb.2016.04.004
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Article ; Online: Novel Coronin7 interactions with Cdc42 and N-WASP regulate actin organization and Golgi morphology.

Bhattacharya, Kurchi / Swaminathan, Karthic / Peche, Vivek S / Clemen, Christoph S / Knyphausen, Philipp / Lammers, Michael / Noegel, Angelika A / Rastetter, Raphael H

Scientific reports

2016 Volume 6, Page(s) 25411

Abstract: The contribution of the actin cytoskeleton to the unique architecture of the Golgi complex is manifold. An important player in this process is Coronin7 (CRN7), a Golgi-resident protein that stabilizes F-actin assembly at the trans-Golgi network (TGN) ... ...

Abstract	The contribution of the actin cytoskeleton to the unique architecture of the Golgi complex is manifold. An important player in this process is Coronin7 (CRN7), a Golgi-resident protein that stabilizes F-actin assembly at the trans-Golgi network (TGN) thereby facilitating anterograde trafficking. Here, we establish that CRN7-mediated association of F-actin with the Golgi apparatus is distinctly modulated via the small Rho GTPase Cdc42 and N-WASP. We identify N-WASP as a novel interaction partner of CRN7 and demonstrate that CRN7 restricts spurious F-actin reorganizations by repressing N-WASP 'hyperactivity' upon constitutive Cdc42 activation. Loss of CRN7 leads to increased cellular F-actin content and causes a concomitant disruption of the Golgi structure. CRN7 harbours a Cdc42- and Rac-interactive binding (CRIB) motif in its tandem β-propellers and binds selectively to GDP-bound Cdc42N17 mutant. We speculate that CRN7 can act as a cofactor for active Cdc42 generation. Mutation of CRIB motif residues that abrogate Cdc42 binding to CRN7 also fail to rescue the cellular defects in fibroblasts derived from CRN7 KO mice. Cdc42N17 overexpression partially rescued the KO phenotypes whereas N-WASP overexpression failed to do so. We conclude that CRN7 spatiotemporally influences F-actin organization and Golgi integrity in a Cdc42- and N-WASP-dependent manner.
Language	English
Publishing date	2016-05-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep25411
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Article ; Online: Dynamic expression patterns of Irx3 and Irx5 during germline nest breakdown and primordial follicle formation promote follicle survival in mouse ovaries.

Fu, Anqi / Oberholtzer, Sydney M / Bagheri-Fam, Stefan / Rastetter, Raphael H / Holdreith, Claire / Caceres, Valeria L / John, Steven V / Shaw, Sarah A / Krentz, Kathleen J / Zhang, Xiaoyun / Hui, Chi-Chung / Wilhelm, Dagmar / Jorgensen, Joan S

PLoS genetics

2018 Volume 14, Issue 8, Page(s) e1007488

Abstract: Women and other mammalian females are born with a finite supply of oocytes that determine their reproductive lifespan. During fetal development, individual oocytes are enclosed by a protective layer of granulosa cells to form primordial follicles that ... ...

Abstract	Women and other mammalian females are born with a finite supply of oocytes that determine their reproductive lifespan. During fetal development, individual oocytes are enclosed by a protective layer of granulosa cells to form primordial follicles that will grow, mature, and eventually release the oocyte for potential fertilization. Despite the knowledge that follicles are dysfunctional and will die without granulosa cell-oocyte interactions, the mechanisms by which these cells establish communication is unknown. We previously identified that two members of the Iroquois homeobox transcription factor gene family, Irx3 and Irx5, are expressed within developing ovaries but not testes. Deletion of both factors (Irx3-Irx5EGFP/Irx3-Irx5EGFP) disrupted granulosa cell-oocyte contact during early follicle development leading to oocyte death. Thus, we hypothesized that Irx3 and Irx5 are required to develop cell-cell communication networks to maintain follicle integrity and female fertility. A series of Irx3 and Irx5 mutant mouse models were generated to assess roles for each factor. While both Irx3 and Irx5 single mutant females were subfertile, their breeding outcomes and ovary histology indicated distinct causes. Careful analysis of Irx3- and Irx5-reporter mice linked the cause of this disparity to dynamic spatio-temporal changes in their expression patterns. Both factors marked the progenitor pre-granulosa cell population in fetal ovaries. At the critical phase of germline nest breakdown and primordial follicle formation however, Irx3 and Irx5 transitioned to oocyte- and granulosa cell-specific expression respectively. Further investigation into the cause of follicle death in Irx3-Irx5EGFP/Irx3-Irx5EGFP ovaries uncovered specific defects in both granulosa cells and oocytes. Granulosa cell defects included poor contributions to basement membrane deposition and mis-localization of gap junction proteins. Granulosa cells and oocytes both presented fewer cell projections resulting in compromised cell-cell communication. Altogether, we conclude that Irx3 and Irx5 first work together to define the pregranulosa cell population of germline nests. During primordial follicle formation, they transition to oocyte- and granulosa cell-specific expression patterns where they cooperate in neighboring cells to build the foundation for follicle integrity. This foundation is left as their legacy of the essential oocyte-granulosa cell communication network that ensures and ultimately optimizes the integrity of the ovarian reserve and therefore, the female reproductive lifespan.
MeSH term(s)	Animals ; Cell Communication ; Connexins/genetics ; Connexins/physiology ; Female ; Gene Expression Regulation, Developmental ; Germ Cells ; Granulosa Cells/physiology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/physiology ; Mice ; Mice, Nude ; Oocytes/physiology ; Transcription Factors/genetics ; Transcription Factors/physiology
Chemical Substances	Connexins ; Homeodomain Proteins ; Irx3 protein, mouse ; Irx5 protein, mouse ; Transcription Factors
Language	English
Publishing date	2018-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1007488
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Article ; Online: WNT/β-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary.

Gustin, Sonja E / Hogg, Kirsten / Stringer, Jessica M / Rastetter, Raphael H / Pelosi, Emanuele / Miles, Denise C / Sinclair, Andrew H / Wilhelm, Dagmar / Western, Patrick S

Developmental biology

2016 Volume 412, Issue 2, Page(s) 250–260

Abstract: Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct ... ...

Abstract	Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct supporting cell populations are present in the ovary, with one providing granulosa cells of the medullary follicles and the other providing granulosa cells of the cortical follicles, the latter of which support lifelong fertility. Here, we demonstrate that XX fetal gonads contain GATA4 expressing supporting cells that either enter mitotic arrest, or remain proliferative. Blocking WNT signalling reduces XX supporting cell proliferation, while stabilising β-catenin signalling promotes proliferation, indicating that the renewal of pre-granulosa cells is dependent on WNT/β-catenin signalling in the proliferative supporting cell population. In contrast, XX supporting cells express p27 and FOXL2 and are maintained in mitotic arrest. Although FOXL2 is required for maintaining high levels of p27 expression, it is dispensable for entry and maintenance of mitotic arrest in XX supporting cells. Combined our data suggest that both medullary and cortical precursors arise from a common GATA4 expressing cell type. In addition, this work indicates that a balance between supporting cell self-renewal and differentiation is maintained in the developing ovary by relative WNT/β-catenin and p27/FOXL2 activities. This study provides significant new insights into the origin and formation of ovarian follicles and evidence supporting a common fetal origin of medullary and cortical granulosa cells.
MeSH term(s)	Animals ; Cell Cycle Checkpoints ; Cell Differentiation ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Female ; Flow Cytometry ; Fluorescent Antibody Technique ; Forkhead Box Protein L2 ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Granulosa Cells/metabolism ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Male ; Mice, 129 Strain ; Mice, Knockout ; Mice, Transgenic ; Octamer Transcription Factor-3/genetics ; Octamer Transcription Factor-3/metabolism ; Ovary/cytology ; Ovary/embryology ; Ovary/metabolism ; Wnt4 Protein/metabolism ; beta Catenin/metabolism
Chemical Substances	Cdkn1b protein, mouse ; Forkhead Box Protein L2 ; Forkhead Transcription Factors ; Foxl2 protein, mouse ; Octamer Transcription Factor-3 ; Pou5f1 protein, mouse ; Wnt4 Protein ; beta Catenin ; Green Fluorescent Proteins (147336-22-9) ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2)
Language	English
Publishing date	2016-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; 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.2016.02.024
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Article: Marker genes identify three somatic cell types in the fetal mouse ovary

Rastetter, Raphael H / Anne-Amandine Chassot / Dagmar Wilhelm / Huijun Chen / James S. Palmer / Marie-Christine Chaboissier / Pascal Bernard / Patrick S. Western / Robert G. Ramsay

Developmental biology. 2014 Oct. 15, v. 394, no. 2

2014

Abstract: The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries ... ...

Abstract	The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility.
Keywords	adult stem cells ; adults ; cell differentiation ; embryogenesis ; female fertility ; females ; genetic markers ; granulosa cells ; loss-of-function mutation ; meiosis ; mice ; molecular biology ; mutants ; oocytes ; oogonia ; ovarian development ; secretion ; sex hormones ; somatic cells
Language	English
Dates of publication	2014-1015
Size	p. 242-252.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2014.08.013
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Article: WNT/Î²-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary

Gustin, Sonja E / Kirsten Hogg / Jessica M. Stringer / Raphael H. Rastetter / Emanuele Pelosi / Denise C. Miles / Andrew H. Sinclair / Dagmar Wilhelm / Patrick S. Western

Developmental biology. 2016 Apr. 15, v. 412

2016

Abstract	Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct supporting cell populations are present in the ovary, with one providing granulosa cells of the medullary follicles and the other providing granulosa cells of the cortical follicles, the latter of which support lifelong fertility. Here, we demonstrate that XX fetal gonads contain GATA4 expressing supporting cells that either enter mitotic arrest, or remain proliferative. Blocking WNT signalling reduces XX supporting cell proliferation, while stabilising Î²-catenin signalling promotes proliferation, indicating that the renewal of pre-granulosa cells is dependent on WNT/Î²-catenin signalling in the proliferative supporting cell population. In contrast, XX supporting cells express p27 and FOXL2 and are maintained in mitotic arrest. Although FOXL2 is required for maintaining high levels of p27 expression, it is dispensable for entry and maintenance of mitotic arrest in XX supporting cells. Combined our data suggest that both medullary and cortical precursors arise from a common GATA4 expressing cell type. In addition, this work indicates that a balance between supporting cell self-renewal and differentiation is maintained in the developing ovary by relative WNT/Î²-catenin and p27/FOXL2 activities. This study provides significant new insights into the origin and formation of ovarian follicles and evidence supporting a common fetal origin of medullary and cortical granulosa cells.
Keywords	GATA transcription factors ; Sertoli cells ; cell proliferation ; granulosa cells ; mitosis ; sexual development
Language	English
Dates of publication	2016-0415
Size	p. 250-260.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2016.02.024
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Article ; Online: Coronin 2A (CRN5) expression is associated with colorectal adenoma-adenocarcinoma sequence and oncogenic signalling.

Rastetter, Raphael H / Blömacher, Margit / Drebber, Uta / Marko, Marija / Behrens, Juliane / Solga, Roxana / Hojeili, Sarah / Bhattacharya, Kurchi / Wunderlich, Claudia M / Wunderlich, F Thomas / Odenthal, Margarete / Ziemann, Anja / Eichinger, Ludwig / Clemen, Christoph S

BMC cancer

2015 Volume 15, Page(s) 638

Abstract: Background: Coronin proteins are known as regulators of actin-based cellular processes, and some of them are associated with the malignant progression of human cancer. Here, we show that expression of coronin 2A is up-regulated in human colon carcinoma.! ...

Abstract	Background: Coronin proteins are known as regulators of actin-based cellular processes, and some of them are associated with the malignant progression of human cancer. Here, we show that expression of coronin 2A is up-regulated in human colon carcinoma. Methods: This study included 26 human colon tumour specimens and 9 normal controls. Expression and localisation of coronin 2A was studied by immunohistochemistry, immunofluorescence imaging, cell fractionation, and immunoblotting. Functional roles of coronin 2A were analysed by over-expression and knock-down of the protein. Protein interactions were studied by co-immunoprecipitation and pull-down experiments, mass spectrometry analyses, and in vitro kinase and methylation assays. Results: Histopathological investigation revealed that the expression of coronin 2A in colon tumour cells is up-regulated during the adenoma-adenocarcinoma progression. At the subcellular level, coronin 2A localised to multiple compartments, i.e. F-actin stress fibres, the front of lamellipodia, focal adhesions, and the nuclei. Over-expression of coronin 2A led to a reduction of F-actin stress fibres and elevated cell migration velocity. We identified two novel direct coronin 2A interaction partners. The interaction of coronin 2A with MAPK14 (mitogen activated protein kinase 14 or MAP kinase p38α) led to phosphorylation of coronin 2A and also to activation of the MAPK14 pathway. Moreover, coronin 2A interacted with PRMT5 (protein arginine N-methyltransferase 5), which modulates the sensitivity of tumour cells to TRAIL-induced cell death. Conclusions: We show that increased expression of coronin 2A is associated with the malignant phenotype of human colon carcinoma. Moreover, we linked coronin 2A to MAPK14 and PRMT5 signalling pathways involved in tumour progression.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Adenoma/genetics ; Adenoma/metabolism ; Adenoma/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Colonic Neoplasms/genetics ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Mitogen-Activated Protein Kinase 14/metabolism ; Phosphorylation ; Protein Transport ; Protein-Arginine N-Methyltransferases/metabolism ; Pseudopodia/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; Signal Transduction ; Stress Fibers/metabolism ; Substrate Specificity
Chemical Substances	Microfilament Proteins ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; coronin proteins (145420-64-0) ; PRMT5 protein, human (EC 2.1.1.319) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; Mitogen-Activated Protein Kinase 14 (EC 2.7.11.24)
Language	English
Publishing date	2015-09-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-015-1645-7
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Article ; Online: Marker genes identify three somatic cell types in the fetal mouse ovary.

Rastetter, Raphael H / Bernard, Pascal / Palmer, James S / Chassot, Anne-Amandine / Chen, Huijun / Western, Patrick S / Ramsay, Robert G / Chaboissier, Marie-Christine / Wilhelm, Dagmar

Developmental biology

2014 Volume 394, Issue 2, Page(s) 242–252

Abstract	The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility.
MeSH term(s)	Animals ; COUP Transcription Factor II/metabolism ; Cell Lineage/physiology ; Female ; Fetus/cytology ; Fluorescent Antibody Technique ; Forkhead Box Protein L2 ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation, Developmental/physiology ; Genetic Markers/genetics ; In Situ Hybridization ; Mice ; Mice, Inbred C57BL ; Ovary/cytology ; Ovary/embryology ; Ovary/metabolism ; Real-Time Polymerase Chain Reaction ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	COUP Transcription Factor II ; Forkhead Box Protein L2 ; Forkhead Transcription Factors ; Foxl2 protein, mouse ; Genetic Markers ; Lgr5 protein, mouse ; Nr2f2 protein, mouse ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2014-10-15
Publishing country	United States
Document type	Journal Article ; 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.2014.08.013
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