The Transcription Factor Rfx3 Regulates [Beta]-Cell Differentiation, Function, and Glucokinase Expression
Pancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing beta-cells. The objective of this work was to unravel the cellular and molecular mechanisms underlying this deficiency. Immunofluorescence studies and quantitative RT-PCR experim...
Saved in:
Published in | Diabetes (New York, N.Y.) Vol. 59; no. 7; p. 1674 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
American Diabetes Association
01.07.2010
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Abstract | Pancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing beta-cells. The objective of this work was to unravel the cellular and molecular mechanisms underlying this deficiency. Immunofluorescence studies and quantitative RT-PCR experiments were used to study the emergence of insulin-positive cells, the expression of transcription factors implicated in the differentiation of beta-cells from endocrine progenitors, and the expression of mature beta-cell markers during development in Rfx3(-/-) and pancreas-specific Rfx3-knockout mice. RNA interference experiments were performed to document the consequences of downregulating Rfx3 expression in Min6 beta-cells. Quantitative chromatin immunoprecipitation (ChIP), ChIP sequencing, and bandshift experiments were used to identify Rfx3 target genes. Reduced development of insulin-positive cells in Rfx3(-/-) mice was not due to deficiencies in endocrine progenitors or beta-lineage specification, but reflected the accumulation of insulin-positive beta-cell precursors and defective beta-cells exhibiting reduced insulin, Glut-2, and Gck expression. Similar incompletely differentiated beta-cells developed in pancreas-specific Rfx3-deficient embryos. Defective beta-cells lacking Glut-2 and Gck expression dominate in Rfx3-deficent adults, leading to glucose intolerance. Attenuated Glut-2 and glucokinase expression, and impaired glucose-stimulated insulin secretion, were also induced by RNA interference-mediated inhibition of Rfx3 expression in Min6 cells. Finally, Rfx3 was found to bind in Min6 cells and human islets to two well-known regulatory sequences, Pal-1 and Pal-2, in the neuroendocrine promoter of the glucokinase gene. Our results show that Rfx3 is required for the differentiation and function of mature beta-cells and regulates the beta-cell promoter of the glucokinase gene. |
---|---|
AbstractList | Pancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing beta-cells. The objective of this work was to unravel the cellular and molecular mechanisms underlying this deficiency. Immunofluorescence studies and quantitative RT-PCR experiments were used to study the emergence of insulin-positive cells, the expression of transcription factors implicated in the differentiation of beta-cells from endocrine progenitors, and the expression of mature beta-cell markers during development in Rfx3(-/-) and pancreas-specific Rfx3-knockout mice. RNA interference experiments were performed to document the consequences of downregulating Rfx3 expression in Min6 beta-cells. Quantitative chromatin immunoprecipitation (ChIP), ChIP sequencing, and bandshift experiments were used to identify Rfx3 target genes. Reduced development of insulin-positive cells in Rfx3(-/-) mice was not due to deficiencies in endocrine progenitors or beta-lineage specification, but reflected the accumulation of insulin-positive beta-cell precursors and defective beta-cells exhibiting reduced insulin, Glut-2, and Gck expression. Similar incompletely differentiated beta-cells developed in pancreas-specific Rfx3-deficient embryos. Defective beta-cells lacking Glut-2 and Gck expression dominate in Rfx3-deficent adults, leading to glucose intolerance. Attenuated Glut-2 and glucokinase expression, and impaired glucose-stimulated insulin secretion, were also induced by RNA interference-mediated inhibition of Rfx3 expression in Min6 cells. Finally, Rfx3 was found to bind in Min6 cells and human islets to two well-known regulatory sequences, Pal-1 and Pal-2, in the neuroendocrine promoter of the glucokinase gene. Our results show that Rfx3 is required for the differentiation and function of mature beta-cells and regulates the beta-cell promoter of the glucokinase gene. |
Author | Bonal, Claire Seguín-Estévez, Queralt Bucher, Philipp Durand, Bénédicte Reith, Walter Ait-Lounis, Aouatef Meda, Paolo Herrera, Pedro L Schmid, Christoph D |
Author_xml | – sequence: 1 givenname: Aouatef surname: Ait-Lounis fullname: Ait-Lounis, Aouatef – sequence: 2 givenname: Claire surname: Bonal fullname: Bonal, Claire – sequence: 3 givenname: Queralt surname: Seguín-Estévez fullname: Seguín-Estévez, Queralt – sequence: 4 givenname: Christoph surname: Schmid middlename: D fullname: Schmid, Christoph D – sequence: 5 givenname: Philipp surname: Bucher fullname: Bucher, Philipp – sequence: 6 givenname: Pedro surname: Herrera middlename: L fullname: Herrera, Pedro L – sequence: 7 givenname: Bénédicte surname: Durand fullname: Durand, Bénédicte – sequence: 8 givenname: Paolo surname: Meda fullname: Meda, Paolo – sequence: 9 givenname: Walter surname: Reith fullname: Reith, Walter |
BookMark | eNqNi8tqwzAQRUVJoc7jH4aua5AliPA2D7fr4EUhhCCccaNEjByNBPn8uiQfUO7iXDj3TsWEAuGLKKpa16VW5nsiCikrVVamNm9iynyRUi7HFMK1Z4Q2WuIuuiG5QNDYLoUIu_6uYYc_2duEDPsVJnso1-g9bFzfY0RKzv49PqDJ1D2apRN8-tyFqyPLCNv7EJF5dHPx2lvPuHhyJt6bbbv-KocYbhk5HS8hRxrV0ShVaaWM1P8a_QK4VEqQ |
CODEN | DIAEAZ |
ContentType | Journal Article |
Copyright | Copyright American Diabetes Association Jul 2010 |
Copyright_xml | – notice: Copyright American Diabetes Association Jul 2010 |
DBID | 3V. 7RV 7X7 7XB 88E 88I 8AF 8AO 8C1 8FE 8FH 8FI 8FJ 8FK 8G5 ABUWG AFKRA AZQEC BBNVY BEC BENPR BHPHI CCPQU DWQXO FYUFA GHDGH GNUQQ GUQSH HCIFZ K9- K9. KB0 LK8 M0R M0S M1P M2O M2P M7P MBDVC NAPCQ PQEST PQQKQ PQUKI PRINS Q9U S0X |
DatabaseName | ProQuest Central (Corporate) ProQuest Nursing & Allied Health Database Health & Medical Collection ProQuest Central (purchase pre-March 2016) Medical Database (Alumni Edition) Science Database (Alumni Edition) STEM Database ProQuest Pharma Collection Public Health Database (Proquest) 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 eLibrary ProQuest Central ProQuest Natural Science Collection ProQuest One Community College ProQuest Central Korea Health Research Premium Collection Health Research Premium Collection (Alumni) ProQuest Central Student Research Library Prep SciTech Premium Collection Consumer Health Database (Alumni Edition) ProQuest Health & Medical Complete (Alumni) Nursing & Allied Health Database (Alumni Edition) Biological Sciences ProQuest Consumer Health Database Health & Medical Collection (Alumni Edition) PML(ProQuest Medical Library) Research Library Science Database (ProQuest) Biological Science Database Research Library (Corporate) Nursing & Allied Health Premium ProQuest One Academic Eastern Edition (DO NOT USE) ProQuest One Academic ProQuest One Academic UKI Edition ProQuest Central China ProQuest Central Basic SIRS Editorial |
DatabaseTitle | Research Library Prep ProQuest Central Student ProQuest Central Essentials SIRS Editorial elibrary ProQuest Health & Medical Complete (Alumni) ProQuest AP Science ProQuest Central (Alumni Edition) SciTech Premium Collection ProQuest One Community College Research Library (Alumni Edition) ProQuest Natural Science Collection ProQuest Pharma Collection ProQuest Family Health (Alumni Edition) ProQuest Central China ProQuest Central Health Research Premium Collection Health and Medicine Complete (Alumni Edition) Natural Science Collection ProQuest Central Korea Biological Science Collection ProQuest Research Library ProQuest Medical Library (Alumni) ProQuest Public Health ProQuest Science Journals (Alumni Edition) ProQuest Biological Science Collection ProQuest Central Basic ProQuest Science Journals ProQuest Family Health ProQuest One Academic Eastern Edition ProQuest Nursing & Allied Health Source ProQuest Hospital Collection Health Research Premium Collection (Alumni) Biological Science Database ProQuest SciTech Collection ProQuest Hospital Collection (Alumni) Nursing & Allied Health Premium ProQuest Health & Medical Complete ProQuest Medical Library ProQuest One Academic UKI Edition ProQuest Nursing & Allied Health Source (Alumni) ProQuest One Academic ProQuest Central (Alumni) |
DatabaseTitleList | Research Library Prep |
Database_xml | – sequence: 1 dbid: BENPR name: AUTh Library subscriptions: ProQuest Central url: https://www.proquest.com/central sourceTypes: Aggregation Database |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Medicine |
EISSN | 1939-327X |
ExternalDocumentID | 2091784751 |
GroupedDBID | --- .55 .XZ 08P 0R~ 18M 29F 2WC 354 3V. 4.4 53G 5GY 5RE 5RS 5VS 6PF 7RV 7X7 7XB 88E 88I 8AF 8AO 8C1 8FE 8FH 8FI 8FJ 8FK 8G5 8GL 8R4 8R5 AAKAS AAQQT AAWTL AAYEP AAYJJ AAYOK ABOCM ABUWG ACGFO ACGOD ACPRK ADBBV ADZCM AEGXH AENEX AERZD AFHIN AFKRA AHMBA AIAGR AIZAD ALIPV ALMA_UNASSIGNED_HOLDINGS AZQEC BAWUL BBNVY BCR BCU BEC BENPR BES BHPHI BKEYQ BKNYI BLC BPHCQ BTFSW BVXVI C1A CCPQU CS3 DIK DU5 DWQXO E3Z EBS EDB EJD EMOBN EX3 F5P FRP FYUFA GICCO GNUQQ GUQSH GX1 H13 HCIFZ HMCUK HZ~ H~9 IAG IAO IEA IHR INH INR IOF IPO ITC K-O K2M K9- K9. KQ8 L7B LK8 M0R M1P M2O M2P M2Q M5~ M7P MBDVC N4W NAPCQ O5R O5S O9- OB3 OHH OK1 OVD P2P PCD PEA PQEST PQQKQ PQUKI PRINS PROAC PSQYO Q2X Q9U RHF RHI RPM S0X SJFOW SJN SV3 TDI TEORI TR2 UKHRP VVN W8F WH7 WOQ WOW X7M YFH YHG YOC ZY1 ~KM |
ID | FETCH-proquest_journals_7221322703 |
IEDL.DBID | 8C1 |
ISSN | 0012-1797 |
IngestDate | Thu Oct 10 18:36:19 EDT 2024 |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 7 |
Language | English |
LinkModel | DirectLink |
MergedId | FETCHMERGED-proquest_journals_7221322703 |
PQID | 722132270 |
PQPubID | 34443 |
ParticipantIDs | proquest_journals_722132270 |
PublicationCentury | 2000 |
PublicationDate | 20100701 |
PublicationDateYYYYMMDD | 2010-07-01 |
PublicationDate_xml | – month: 07 year: 2010 text: 20100701 day: 01 |
PublicationDecade | 2010 |
PublicationPlace | New York |
PublicationPlace_xml | – name: New York |
PublicationTitle | Diabetes (New York, N.Y.) |
PublicationYear | 2010 |
Publisher | American Diabetes Association |
Publisher_xml | – name: American Diabetes Association |
SSID | ssj0006060 |
Score | 4.016113 |
Snippet | Pancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing beta-cells. The objective of this... |
SourceID | proquest |
SourceType | Aggregation Database |
StartPage | 1674 |
SubjectTerms | Cells Diabetes Experiments Glucagon Glucose Insulin Pancreas Research design Transcription factors |
Title | The Transcription Factor Rfx3 Regulates [Beta]-Cell Differentiation, Function, and Glucokinase Expression |
URI | https://www.proquest.com/docview/722132270 |
Volume | 59 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV3dS8MwED_cBuKL-Ik6LUF8NLh-xj2Jq61D2JCiUBAZzUdhbGRqK-zPN2lSfRD2FiiEctfc7673u_wArkIaqTQ_JLigXKgChXF8OxQediMmdIZBKNWzw5NpNH4NnvIwt9ycytIq25jYBGq-Yvof-Q3xPF04kcHdxyfWolG6uWoVNDrQczXO6UHx-I_hoXJzM4HievoWTvIv3DYYku7Brk3-0L3x1j5sCXkA2xPb3j6EuXIaatCjPcsobfRwUFaufZQZ3XhRobeRqIt3HIvlEj1YiZPaGPkapQqqzKqQHD1qTvpiLhVaoWRtaa_yCC7T5CUe4_ZVZ_ajqma_JvCPoStXUpwAKtWBC0rmuoywoKCqgCJ-4Q_E0OeC0oidQn_DRmcbn_Zhx_TKNTn1HLr117e4UBBcUwc6JCdOY24HeqNk-pz9AA-wkUM |
link.rule.ids | 314,780,784,12056,12223,21388,31719,33266,33744,43310,43579,43805,73745,74014,74302 |
linkProvider | ProQuest |
linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1LSwMxEB60gnoRn6j1EcSjwe4z7Ul07bpqt4dSoSCyJNksFEuq7gr9-SabrB6E3gKBECbJfDOZL_kALgMWqjA_IJiyXKgEhee42xMudkIudIRBGNNvh9NhmLz4T5NgYrk5paVVNj6xdtT5nOs78mviujpxIp2bj0-sRaN0cdUqaKzCmkJ9ojd1N_pjeKjY3LxAcVz9Cyf5525rDIm3YcsGf-jWrNYOrAi5C-upLW_vwVQtGqrRoznLKK71cNCoWHhoZHTjRYle70RF33AkZjN0byVOKmPkKxQrqDItKnP0oDnp71Op0Ar1F5b2KvfhIu6PowQ3U83spiqzXxN4B9CScykOARXqwPkFdxxOuE-ZSqCIR72O6Hm5YCzkR9BeMtDx0t5z2EjG6SAbPA6f27Bp6uaaqHoCrerrW5wqOK7YWW30HyDVkb4 |
linkToPdf | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1LSwMxEB60QvEiPrHWRxCPhnafaU-i26710SJFoSBSNtlZKJZU3RX68002WT0IvQUWwjJJ5pvJfJkP4CLgoQrzA0YTnqJKUERKO110qRMK1BEG41y_HR6OwsGLfz8JJralUG5plZVPLB11uhD6jrzFXFcnTqzdyiwr4qkXX318Ui0gpQutVk1jHTa0yJxuo9-J_tgeKk43r1EcV3fkZP9cb4kn8TZs2UCQXJuV24E1lLtQH9pS9x7M1AKSEkmqc03iUhuHjLOlR8ZGQx5z8nqDRfJGI5zPSc_KnRTG4JckVrBlRolMya3mp7_PpEIu0l9aCqzch_O4_xwNaPWrU7vB8umvObwDqMmFxEMgmTp8fiYcRzDhJ1wlU8xLvDZ2vRQ5D0UDmismOlr59Qzqyt7Tx7vRQxM2TQldc1aPoVZ8feOJQuaCn5Y2_wESX5Xj |
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=The+Transcription+Factor+Rfx3+Regulates+%5BBeta%5D-Cell+Differentiation%2C+Function%2C+and+Glucokinase+Expression&rft.jtitle=Diabetes+%28New+York%2C+N.Y.%29&rft.au=Ait-Lounis%2C+Aouatef&rft.au=Bonal%2C+Claire&rft.au=Segu%C3%ADn-Est%C3%A9vez%2C+Queralt&rft.au=Schmid%2C+Christoph+D&rft.date=2010-07-01&rft.pub=American+Diabetes+Association&rft.issn=0012-1797&rft.eissn=1939-327X&rft.volume=59&rft.issue=7&rft.spage=1674&rft.externalDBID=HAS_PDF_LINK&rft.externalDocID=2091784751 |
thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0012-1797&client=summon |
thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0012-1797&client=summon |
thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0012-1797&client=summon |