Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells
Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to...
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| Veröffentlicht in: | Development (Cambridge) 2012-02, Vol.139 (3), p.488-497 |
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| creator | VanDussen, Kelli L Carulli, Alexis J Keeley, Theresa M Patel, Sanjeevkumar R Puthoff, Brent J Magness, Scott T Tran, Ivy T Maillard, Ivan Siebel, Christian Kolterud, Åsa Grosse, Ann S Gumucio, Deborah L Ernst, Stephen A Tsai, Yu-Hwai Dempsey, Peter J Samuelson, Linda C |
| description | Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis. |
| doi_str_mv | 10.1242/dev.070763 |
| format | Article |
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We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis.</description><identifier>ISSN: 0950-1991</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.070763</identifier><identifier>PMID: 22190634</identifier><language>eng</language><publisher>England: Company of Biologists</publisher><subject>Animals ; Apoptosis - drug effects ; Base Sequence ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Cell Differentiation ; Cell Proliferation ; Development and Stem Cells ; Gene Expression Regulation ; Goblet Cells - metabolism ; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism ; Intestine, Small - cytology ; Intestine, Small - drug effects ; Intestine, Small - metabolism ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Organ Culture Techniques ; Paneth Cells - metabolism ; Promoter Regions, Genetic ; Receptor, Notch1 - antagonists & inhibitors ; Receptor, Notch1 - metabolism ; Receptor, Notch2 - antagonists & inhibitors ; Receptor, Notch2 - metabolism ; Signal Transduction ; Stem Cells - cytology ; Stem Cells - physiology</subject><ispartof>Development (Cambridge), 2012-02, Vol.139 (3), p.488-497</ispartof><rights>2012.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-2e41890a80afb651045e83e06ea56fcd452978ff77e6ecf69db105a1444ee8733</citedby><cites>FETCH-LOGICAL-c513t-2e41890a80afb651045e83e06ea56fcd452978ff77e6ecf69db105a1444ee8733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,551,777,781,882,3665,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22190634$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:123879185$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>VanDussen, Kelli L</creatorcontrib><creatorcontrib>Carulli, Alexis J</creatorcontrib><creatorcontrib>Keeley, Theresa M</creatorcontrib><creatorcontrib>Patel, Sanjeevkumar R</creatorcontrib><creatorcontrib>Puthoff, Brent J</creatorcontrib><creatorcontrib>Magness, Scott T</creatorcontrib><creatorcontrib>Tran, Ivy T</creatorcontrib><creatorcontrib>Maillard, Ivan</creatorcontrib><creatorcontrib>Siebel, Christian</creatorcontrib><creatorcontrib>Kolterud, Åsa</creatorcontrib><creatorcontrib>Grosse, Ann S</creatorcontrib><creatorcontrib>Gumucio, Deborah L</creatorcontrib><creatorcontrib>Ernst, Stephen A</creatorcontrib><creatorcontrib>Tsai, Yu-Hwai</creatorcontrib><creatorcontrib>Dempsey, Peter J</creatorcontrib><creatorcontrib>Samuelson, Linda C</creatorcontrib><title>Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells</title><title>Development (Cambridge)</title><addtitle>Development</addtitle><description>Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Base Sequence</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Cell Differentiation</subject><subject>Cell Proliferation</subject><subject>Development and Stem Cells</subject><subject>Gene Expression Regulation</subject><subject>Goblet Cells - metabolism</subject><subject>Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism</subject><subject>Intestine, Small - cytology</subject><subject>Intestine, Small - drug effects</subject><subject>Intestine, Small - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Sequence Data</subject><subject>Organ Culture Techniques</subject><subject>Paneth Cells - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>Receptor, Notch1 - antagonists & inhibitors</subject><subject>Receptor, Notch1 - metabolism</subject><subject>Receptor, Notch2 - antagonists & inhibitors</subject><subject>Receptor, Notch2 - metabolism</subject><subject>Signal Transduction</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - physiology</subject><issn>0950-1991</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqFkUuLFDEUhYMoTtu68QdIdoJQY96pbAQZxgcMutF1SKduuqNVSZtUjcy_N021g7MSAknu_e4hJwehl5RcUibY2wFuL4kmWvFHaEOF1p2hzDxGG2Ik6agx9AI9q_UHIYQrrZ-iC8aoIYqLDTp8ybM_4Br3yY0x7fGUh2V0M1R8LHmMAYqbY07YpQEPMbQ7pDmutRxwTA2dYxvGvtwdZ7xzFbDP4zIlV3CdYcIexrE-R0-CGyu8OO9b9P3D9berT93N14-fr97fdF5SPncMBO0NcT1xYackJUJCz4EocFIFPwjJjO5D0BoU-KDMsKNEOiqEAOg151vUrbr1NxyXnT2WOLlyZ7OL9lz62U5gJTdGy8a_W_nWmWDwzV1x44Oxh50UD3afby1nkvG2tuj1WaDkX0v7DDvFerLsEuSlWsOINj1T_f9JKpQ-qTbyzUr6kmstEO7fQ4k9ZW5b5nbNvMGv_nVwj_4Nmf8BLGWrFg</recordid><startdate>20120201</startdate><enddate>20120201</enddate><creator>VanDussen, Kelli L</creator><creator>Carulli, Alexis J</creator><creator>Keeley, Theresa M</creator><creator>Patel, Sanjeevkumar R</creator><creator>Puthoff, Brent J</creator><creator>Magness, Scott T</creator><creator>Tran, Ivy T</creator><creator>Maillard, Ivan</creator><creator>Siebel, Christian</creator><creator>Kolterud, Åsa</creator><creator>Grosse, Ann S</creator><creator>Gumucio, Deborah L</creator><creator>Ernst, Stephen A</creator><creator>Tsai, Yu-Hwai</creator><creator>Dempsey, Peter J</creator><creator>Samuelson, Linda C</creator><general>Company of Biologists</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20120201</creationdate><title>Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells</title><author>VanDussen, Kelli L ; Carulli, Alexis J ; Keeley, Theresa M ; Patel, Sanjeevkumar R ; Puthoff, Brent J ; Magness, Scott T ; Tran, Ivy T ; Maillard, Ivan ; Siebel, Christian ; Kolterud, Åsa ; Grosse, Ann S ; Gumucio, Deborah L ; Ernst, Stephen A ; Tsai, Yu-Hwai ; Dempsey, Peter J ; Samuelson, Linda C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-2e41890a80afb651045e83e06ea56fcd452978ff77e6ecf69db105a1444ee8733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Base Sequence</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Cell Differentiation</topic><topic>Cell Proliferation</topic><topic>Development and Stem Cells</topic><topic>Gene Expression Regulation</topic><topic>Goblet Cells - metabolism</topic><topic>Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism</topic><topic>Intestine, Small - cytology</topic><topic>Intestine, Small - drug effects</topic><topic>Intestine, Small - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Sequence Data</topic><topic>Organ Culture Techniques</topic><topic>Paneth Cells - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>Receptor, Notch1 - antagonists & inhibitors</topic><topic>Receptor, Notch1 - metabolism</topic><topic>Receptor, Notch2 - antagonists & inhibitors</topic><topic>Receptor, Notch2 - metabolism</topic><topic>Signal Transduction</topic><topic>Stem Cells - cytology</topic><topic>Stem Cells - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>VanDussen, Kelli L</creatorcontrib><creatorcontrib>Carulli, Alexis J</creatorcontrib><creatorcontrib>Keeley, Theresa M</creatorcontrib><creatorcontrib>Patel, Sanjeevkumar R</creatorcontrib><creatorcontrib>Puthoff, Brent J</creatorcontrib><creatorcontrib>Magness, Scott T</creatorcontrib><creatorcontrib>Tran, Ivy T</creatorcontrib><creatorcontrib>Maillard, Ivan</creatorcontrib><creatorcontrib>Siebel, Christian</creatorcontrib><creatorcontrib>Kolterud, Åsa</creatorcontrib><creatorcontrib>Grosse, Ann S</creatorcontrib><creatorcontrib>Gumucio, Deborah L</creatorcontrib><creatorcontrib>Ernst, Stephen A</creatorcontrib><creatorcontrib>Tsai, Yu-Hwai</creatorcontrib><creatorcontrib>Dempsey, Peter J</creatorcontrib><creatorcontrib>Samuelson, Linda C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Development (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>VanDussen, Kelli L</au><au>Carulli, Alexis J</au><au>Keeley, Theresa M</au><au>Patel, Sanjeevkumar R</au><au>Puthoff, Brent J</au><au>Magness, Scott T</au><au>Tran, Ivy T</au><au>Maillard, Ivan</au><au>Siebel, Christian</au><au>Kolterud, Åsa</au><au>Grosse, Ann S</au><au>Gumucio, Deborah L</au><au>Ernst, Stephen A</au><au>Tsai, Yu-Hwai</au><au>Dempsey, Peter J</au><au>Samuelson, Linda C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells</atitle><jtitle>Development (Cambridge)</jtitle><addtitle>Development</addtitle><date>2012-02-01</date><risdate>2012</risdate><volume>139</volume><issue>3</issue><spage>488</spage><epage>497</epage><pages>488-497</pages><issn>0950-1991</issn><eissn>1477-9129</eissn><abstract>Notch signaling is known to regulate the proliferation and differentiation of intestinal stem and progenitor cells; however, direct cellular targets and specific functions of Notch signals had not been identified. We show here in mice that Notch directly targets the crypt base columnar (CBC) cell to maintain stem cell activity. Notch inhibition induced rapid CBC cell loss, with reduced proliferation, apoptotic cell death and reduced efficiency of organoid initiation. Furthermore, expression of the CBC stem cell-specific marker Olfm4 was directly dependent on Notch signaling, with transcription activated through RBP-Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitors into secretory cell types, including large numbers of cells that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1-deficient intestine demonstrated that the cellular changes were dependent on Atoh1, whereas Notch regulation of Olfm4 gene expression was Atoh1 independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice to control epithelial cell homeostasis.</abstract><cop>England</cop><pub>Company of Biologists</pub><pmid>22190634</pmid><doi>10.1242/dev.070763</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Development (Cambridge), 2012-02, Vol.139 (3), p.488-497 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SWEPUB Freely available online; Alma/SFX Local Collection; Company of Biologists |
| subjects | Animals Apoptosis - drug effects Base Sequence Basic Helix-Loop-Helix Transcription Factors - genetics Cell Differentiation Cell Proliferation Development and Stem Cells Gene Expression Regulation Goblet Cells - metabolism Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism Intestine, Small - cytology Intestine, Small - drug effects Intestine, Small - metabolism Mice Mice, Inbred C57BL Molecular Sequence Data Organ Culture Techniques Paneth Cells - metabolism Promoter Regions, Genetic Receptor, Notch1 - antagonists & inhibitors Receptor, Notch1 - metabolism Receptor, Notch2 - antagonists & inhibitors Receptor, Notch2 - metabolism Signal Transduction Stem Cells - cytology Stem Cells - physiology |
| title | Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells |
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