Apc modulates embryonic stem-cell differentiation by controlling the dosage of [beta]-catenin signaling
The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and t...
Saved in:
Published in | Nature genetics Vol. 32; no. 4; p. 594 |
---|---|
Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group
01.12.2002
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Abstract | The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and tumorigenesis in the adult organism. The adenomatous polyposis coli gene (APC) is a major controller of the Wnt pathway and is essential to prevent tumorigenesis in a variety of tissues and organs. Here, we have investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Catnb also affects the differentiation potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supports the differentiation defects at the molecular level and pinpoints a large number of downstream structural and regulating genes. Chimeric experiments showed that this effect is cell-autonomous. Our results imply that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues. |
---|---|
AbstractList | The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination. Tight somatic regulation of this signal is essential, as uncontrolled nuclear accumulation of beta-catenin can cause developmental defects and tumorigenesis in the adult organism. The adenomatous polyposis coli gene (APC) is a major controller of the Wnt pathway and is essential to prevent tumorigenesis in a variety of tissues and organs. Here, we have investigated the effect of different mutations in Apc on the differentiation potential of mouse embryonic stem (ES) cells. We provide genetic and molecular evidence that the ability and sensitivity of ES cells to differentiate into the three germ layers is inhibited by increased doses of beta-catenin by specific Apc mutations. These range from a severe differentiation blockade in Apc alleles completely deficient in beta-catenin regulation to more specific neuroectodermal, dorsal mesodermal and endodermal defects in more hypomorphic alleles. Accordingly, a targeted oncogenic mutation in Catnb also affects the differentiation potential of ES cells. Expression profiling of wildtype and Apc-mutated teratomas supports the differentiation defects at the molecular level and pinpoints a large number of downstream structural and regulating genes. Chimeric experiments showed that this effect is cell-autonomous. Our results imply that constitutive activation of the Apc/beta-catenin signaling pathway results in differentiation defects in tissue homeostasis, and possibly underlies tumorigenesis in the colon and other self-renewing tissues. |
Author | Fodde, Riccardo Nicole van Poppel Sandra van Leeuwen Gaspar, Claudia Rindapää, Maaret Smits, Ron Kielman, Menno F Roberts, Scott Breukel, Cor Taketo, Makoto Mark |
Author_xml | – sequence: 1 givenname: Menno surname: Kielman middlename: F fullname: Kielman, Menno F – sequence: 2 givenname: Maaret surname: Rindapää fullname: Rindapää, Maaret – sequence: 3 givenname: Claudia surname: Gaspar fullname: Gaspar, Claudia – sequence: 4 fullname: Nicole van Poppel – sequence: 5 givenname: Cor surname: Breukel fullname: Breukel, Cor – sequence: 6 fullname: Sandra van Leeuwen – sequence: 7 givenname: Makoto surname: Taketo middlename: Mark fullname: Taketo, Makoto Mark – sequence: 8 givenname: Scott surname: Roberts fullname: Roberts, Scott – sequence: 9 givenname: Ron surname: Smits fullname: Smits, Ron – sequence: 10 givenname: Riccardo surname: Fodde fullname: Fodde, Riccardo |
BookMark | eNqNzkFOwzAQBVCraqW2lJ5hxN5gN24algiBOEB3CFWOMzGunJnWdha9PUHiAKz-Xzx9_bWYExMKsdXqUauqeSKvldnPxErvTS31QTfzqataS6OqeinWOZ-V0saoZiX8y8XBwN0YbcEMOLTpxhQc5IKDdBgjdKHvMSGVYEtggvYGjqkkjjGQh_KN0HG2HoF7-Gyx2C_ppjUKBDl4sr9sIxa9jRnv__JOPLy_HV8_5CXxdcRcTmce02Tzabebzj1Xh7r6F_oBvHBN8w |
ContentType | Journal Article |
Copyright | Copyright Nature Publishing Group Dec 2002 |
Copyright_xml | – notice: Copyright Nature Publishing Group Dec 2002 |
DBID | 3V. 7QL 7QP 7QR 7SS 7T7 7TK 7TM 7U9 7X7 7XB 88A 88E 8AO 8C1 8FD 8FE 8FH 8FI 8FJ 8FK 8G5 ABUWG AFKRA AZQEC BBNVY BENPR BHPHI C1K CCPQU DWQXO FR3 FYUFA GHDGH GNUQQ GUQSH H94 HCIFZ K9. LK8 M0S M1P M2O M7N M7P MBDVC P64 PQEST PQQKQ PQUKI Q9U RC3 |
DOI | 10.1038/ng1045 |
DatabaseName | ProQuest Central (Corporate) Bacteriology Abstracts (Microbiology B) Calcium & Calcified Tissue Abstracts Chemoreception Abstracts Entomology Abstracts (Full archive) Industrial and Applied Microbiology Abstracts (Microbiology A) Neurosciences Abstracts Nucleic Acids Abstracts Virology and AIDS Abstracts ProQuest Health & Medical Collection ProQuest Central (purchase pre-March 2016) Biology Database (Alumni Edition) Medical Database (Alumni Edition) ProQuest Pharma Collection ProQuest Public Health Database Technology Research Database ProQuest SciTech Collection ProQuest Natural Science Collection Hospital Premium Collection Hospital Premium Collection (Alumni Edition) ProQuest Central (Alumni) (purchase pre-March 2016) Research Library (Alumni Edition) ProQuest Central (Alumni) ProQuest Central ProQuest Central Essentials Biological Science Collection ProQuest Central ProQuest Natural Science Collection Environmental Sciences and Pollution Management ProQuest One Community College ProQuest Central Engineering Research Database Health Research Premium Collection Health Research Premium Collection (Alumni) ProQuest Central Student Research Library Prep AIDS and Cancer Research Abstracts SciTech Premium Collection ProQuest Health & Medical Complete (Alumni) Biological Sciences Health & Medical Collection (Alumni Edition) Medical Database ProQuest Research Library Algology Mycology and Protozoology Abstracts (Microbiology C) Biological Science Database Research Library (Corporate) Biotechnology and BioEngineering Abstracts ProQuest One Academic Eastern Edition (DO NOT USE) ProQuest One Academic ProQuest One Academic UKI Edition ProQuest Central Basic Genetics Abstracts |
DatabaseTitle | Research Library Prep ProQuest Central Student Technology Research Database ProQuest Central Essentials Nucleic Acids Abstracts ProQuest Health & Medical Complete (Alumni) ProQuest Central (Alumni Edition) SciTech Premium Collection ProQuest One Community College Research Library (Alumni Edition) ProQuest Natural Science Collection ProQuest Pharma Collection Environmental Sciences and Pollution Management ProQuest Biology Journals (Alumni Edition) ProQuest Central Genetics Abstracts Health Research Premium Collection Health and Medicine Complete (Alumni Edition) Natural Science Collection ProQuest Central Korea Bacteriology Abstracts (Microbiology B) Algology Mycology and Protozoology Abstracts (Microbiology C) Biological Science Collection AIDS and Cancer Research Abstracts ProQuest Research Library Chemoreception Abstracts Industrial and Applied Microbiology Abstracts (Microbiology A) ProQuest Medical Library (Alumni) ProQuest Public Health Virology and AIDS Abstracts ProQuest Biological Science Collection ProQuest Central Basic ProQuest One Academic Eastern Edition ProQuest Hospital Collection Health Research Premium Collection (Alumni) Biological Science Database ProQuest SciTech Collection Neurosciences Abstracts ProQuest Hospital Collection (Alumni) Biotechnology and BioEngineering Abstracts Entomology Abstracts ProQuest Health & Medical Complete ProQuest Medical Library ProQuest One Academic UKI Edition Engineering Research Database ProQuest One Academic Calcium & Calcified Tissue Abstracts ProQuest Central (Alumni) |
DatabaseTitleList | Research Library Prep |
Database_xml | – sequence: 1 dbid: BENPR name: ProQuest Central url: https://www.proquest.com/central sourceTypes: Aggregation Database |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Biology |
EISSN | 1546-1718 |
ExternalDocumentID | 1028443471 |
GroupedDBID | --- -DZ -~X .55 .GJ 0R~ 123 29M 2FS 36B 39C 3O- 3V. 4.4 53G 5BI 5RE 7QL 7QP 7QR 7SS 7T7 7TK 7TM 7U9 7X7 7XB 85S 88A 88E 8AO 8C1 8FD 8FE 8FH 8FI 8FJ 8FK 8G5 8R4 8R5 AAEEF AAHBH AARCD ABAWZ ABCQX ABDBF ABEFU ABJNI ABLJU ABOCM ABTAH ABUWG ABVXF ACGFO ACGFS ACIWK ACMJI ACNCT ACPRK ADBBV ADFRT AENEX AFFNX AFKRA AFRAH AFSHS AGAYW AGCDD AGEZK AGHTU AHBCP AHMBA AHSBF ALFFA ALIPV ALMA_UNASSIGNED_HOLDINGS AMTXH ASPBG AVWKF AXYYD AZFZN AZQEC B0M BBNVY BENPR BHPHI BKKNO BPHCQ BVXVI C1K CCPQU CS3 DB5 DU5 DWQXO EAD EAP EBC EBD EBS EJD EMB EMK EMOBN EPL ESX EXGXG F5P FEDTE FQGFK FR3 FSGXE FYUFA G8K GNUQQ GUQSH GX1 H94 HCIFZ HMCUK HVGLF HZ~ IAO IH2 IHR INH INR IOV ISR ITC K9. L7B LK8 M0L M1P M2O M7N M7P MBDVC MVM N9A P2P P64 PQEST PQQKQ PQUKI PROAC PSQYO Q2X Q9U RC3 RIG RNT RNTTT SJN SNYQT SV3 TAOOD TBHMF TDRGL TN5 TSG TUS UKHRP VQA X7M XJT XOL Y6R YHZ ZGI ZXP ZY4 ~8M ~KM |
ID | FETCH-proquest_journals_2201493763 |
IEDL.DBID | 7X7 |
ISSN | 1061-4036 |
IngestDate | Thu Oct 10 20:59:19 EDT 2024 |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 4 |
Language | English |
LinkModel | DirectLink |
MergedId | FETCHMERGED-proquest_journals_2201493763 |
PQID | 220149376 |
PQPubID | 33429 |
ParticipantIDs | proquest_journals_220149376 |
PublicationCentury | 2000 |
PublicationDate | 20021201 |
PublicationDateYYYYMMDD | 2002-12-01 |
PublicationDate_xml | – month: 12 year: 2002 text: 20021201 day: 01 |
PublicationDecade | 2000 |
PublicationPlace | New York |
PublicationPlace_xml | – name: New York |
PublicationTitle | Nature genetics |
PublicationYear | 2002 |
Publisher | Nature Publishing Group |
Publisher_xml | – name: Nature Publishing Group |
SSID | ssj0014408 |
Score | 3.466552 |
Snippet | The Wnt signal-transduction pathway induces the nuclear translocation of membrane-bound beta-catenin (Catnb) and has a key role in cell-fate determination.... |
SourceID | proquest |
SourceType | Aggregation Database |
StartPage | 594 |
SubjectTerms | Cell differentiation Kinases Mutation Proteins Stem cells Tissues Translocation Tumorigenesis |
Title | Apc modulates embryonic stem-cell differentiation by controlling the dosage of [beta]-catenin signaling |
URI | https://www.proquest.com/docview/220149376 |
Volume | 32 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1LS8NAEB60RfAiPlGrZRCvockm2aQnqaWlCBYRhYBI2c1ui4du2iYe8u_daZJehF5y2RDC7Ow8v9kP4DHup1YNROi4ERNOkPbtmaNZGS-ImGZu6nNNdcjXKZ98Bi9JmNTYnLyGVTY2cWuoVZZSjbzHGAXz9jg8rdYOkUZRc7Vm0DiEtsdsLGHVOUp2-Ra1LatJOE5pEnUpK2ohP-6ZhU1Dwn_2d-tUxqdwUkeDOKi27wwOtDmHo4ofsryAxWCV4jJTRLGlc9RLuSnpKluk25cdqrljQ3BSVCJGWWKNPqc5c7ThHaqMwGOYzfFL6kJ8OwSCMj8GCbsh6LVLeBiPPoYTp_nPWa1i-WwnEP8KWiYz-hqQKz7nggXK09b1Sk7uR3lKyFT6vo3UbqCz50O3e1c7cNwwobjeHbSKza--tw65kN2t2O0zHnpdaD-Ppm_vf5Jbkz4 |
link.rule.ids | 315,786,790,12083,12250,21416,27955,27956,31752,33299,33777,43343,43612,43838,74100,74369,74657 |
linkProvider | ProQuest |
linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1LS8NAEB60InoRn6j1MYjX0CSbbNqTFLFEbXuqEBAJ2UeLhya1iYf8e3fy6EXoeZdl2Z2d5zf7ATz2B9KIQeJbduAmlicH5s1Rr4zjBa52bcm4pjzkZMrDD-8t8qMGm5M3sMpWJ1aKWmWScuQ91yVn3jyHp9WPRaRRVFxtGDR2Yc9jzCMxD6JNvEVly7oTjlOYRFXKmlqI9XvpwoQh_j_9WxmV0TEcNd4gDuvrO4EdnZ7Cfs0PWZ7BYriSuMwUUWzpHPVSrEv6yhbp92WLcu7YEpwU9RGjKLFBn1OfORr3DlVG4DHM5vgpdJF8WQSCSr9TJOxGQtPO4WH0MnsOrXafcSNiebw5EHYBnTRL9SUgV3zOE9dTjjamV3AyP8pRiZCCMeOpXUF3y0LXW0fv4SCcTcbx-HX63oXDlhXFdm6gU6x_9a0xzoW4q67gD4m4k8Q |
linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1LS8NAEB60ongRn6j1MYjXkPemPUlRQ30VDwoBkZDNbkoPTWoTD_n37iSbXoSeNyxhdnee38wHcDsYpuoaJL5hBU5ieOlQvTnqlbG9wJGOlbpMUh7ybcLGn95z5Ed6pFCpYZWdTmwUtShSypGbjkPOvHoOZqZREe8P4d3ixyACKSq0ajaNTdhSRtIiFocgWsVeVMJsu-IYhUxUsWxphtyBmU9VSOL_08WNgQn3YU97hjhqj_IANmR-CNstV2R9BNPRIsV5IYhuS5Yo53xZ01hbpEnMBuXfsSM7qVpxI69RI9Gp5xyVq4eiICAZFhl-cVkl3wYBovJZjoTjSOizY7gJHz_ux0b3n7G-bmW8Eo57Ar28yOUpIBMsY4njCVsqM8wZmSJhi4Sn3HWV13YG_TUbna9dvYYdJf349Wny0ofdjiDFsi-gVy1_5aWy0xW_ak7gD7c0l_A |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Apc+modulates+embryonic+stem-cell+differentiation+by+controlling+the+dosage+of+%5Bbeta%5D-catenin+signaling&rft.jtitle=Nature+genetics&rft.au=Kielman%2C+Menno+F&rft.au=Rindap%C3%A4%C3%A4%2C+Maaret&rft.au=Gaspar%2C+Claudia&rft.au=Nicole+van+Poppel&rft.date=2002-12-01&rft.pub=Nature+Publishing+Group&rft.issn=1061-4036&rft.eissn=1546-1718&rft.volume=32&rft.issue=4&rft.spage=594&rft_id=info:doi/10.1038%2Fng1045&rft.externalDBID=HAS_PDF_LINK&rft.externalDocID=1028443471 |
thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1061-4036&client=summon |
thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1061-4036&client=summon |
thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1061-4036&client=summon |