Tcf/Lef repressors differentially regulate Shh-Gli target gene activation thresholds to generate progenitor patterning in the developing CNS
During neural tube development, Shh signaling through Gli transcription factors is necessary to establish five distinct ventral progenitor domains that give rise to unique classes of neurons and glia that arise in specific positions along the dorsoventral axis. These cells are generated from progeni...
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description | During neural tube development, Shh signaling through Gli transcription factors is necessary to establish five distinct ventral progenitor domains that give rise to unique classes of neurons and glia that arise in specific positions along the dorsoventral axis. These cells are generated from progenitors that display distinct transcription factor gene expression profiles in specific domains in the ventricular zone. However, the molecular genetic mechanisms that control the differential spatiotemporal transcriptional responses of progenitor target genes to graded Shh-Gli signaling remain unclear. The current study demonstrates a role for Tcf/Lef repressor activity in this process. We show that Tcf3 and Tcf7L2 (Tcf4) are required for proper ventral patterning and function by independently regulating two Shh-Gli target genes, Nkx2.2 and Olig2, which are initially induced in a common pool of progenitors that ultimately segregate into unique territories giving rise to distinct progeny. Genetic and functional studies in vivo show that Tcf transcriptional repressors selectively elevate the strength and duration of Gli activity necessary to induce Nkx2.2, but have no effect on Olig2, and thereby contribute to the establishment of their distinct expression domains in cooperation with graded Shh signaling. Together, our data reveal a Shh-Gli-independent transcriptional input that is required to shape the precise spatial and temporal response to extracellular morphogen signaling information during lineage segregation in the CNS. |
doi_str_mv | 10.1242/dev.068270 |
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These cells are generated from progenitors that display distinct transcription factor gene expression profiles in specific domains in the ventricular zone. However, the molecular genetic mechanisms that control the differential spatiotemporal transcriptional responses of progenitor target genes to graded Shh-Gli signaling remain unclear. The current study demonstrates a role for Tcf/Lef repressor activity in this process. We show that Tcf3 and Tcf7L2 (Tcf4) are required for proper ventral patterning and function by independently regulating two Shh-Gli target genes, Nkx2.2 and Olig2, which are initially induced in a common pool of progenitors that ultimately segregate into unique territories giving rise to distinct progeny. Genetic and functional studies in vivo show that Tcf transcriptional repressors selectively elevate the strength and duration of Gli activity necessary to induce Nkx2.2, but have no effect on Olig2, and thereby contribute to the establishment of their distinct expression domains in cooperation with graded Shh signaling. Together, our data reveal a Shh-Gli-independent transcriptional input that is required to shape the precise spatial and temporal response to extracellular morphogen signaling information during lineage segregation in the CNS.</description><identifier>ISSN: 0950-1991</identifier><identifier>ISSN: 1477-9129</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.068270</identifier><identifier>PMID: 21775418</identifier><language>eng</language><publisher>England: Company of Biologists</publisher><subject>Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Basic Helix-Loop-Helix Transcription Factors - metabolism ; Body Patterning - genetics ; Body Patterning - physiology ; Central Nervous System - cytology ; Central Nervous System - embryology ; Central Nervous System - metabolism ; Chick Embryo ; Chromatin Immunoprecipitation ; Electroporation ; Enhancer Elements, Genetic - genetics ; Enhancer Elements, Genetic - physiology ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; In Situ Hybridization ; Medicin och hälsovetenskap ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Oligodendrocyte Transcription Factor 2 ; Polymerase Chain Reaction ; Spinal Cord - cytology ; Spinal Cord - embryology ; Spinal Cord - metabolism ; Stem Cells - cytology ; Stem Cells - metabolism ; Transcription Factor 4 ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Development (Cambridge), 2011-09, Vol.138 (17), p.3711-3721</ispartof><rights>2011.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c563t-f115b26ea8c3e6d1400fe93c1ab8c327711a42e85b43f022600b48a60fcf8c7c3</citedby><cites>FETCH-LOGICAL-c563t-f115b26ea8c3e6d1400fe93c1ab8c327711a42e85b43f022600b48a60fcf8c7c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,552,780,784,885,3678,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21775418$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:123037712$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Lei, Qiubo</creatorcontrib><creatorcontrib>Oosterveen, Tony</creatorcontrib><creatorcontrib>Ericson, Johan</creatorcontrib><creatorcontrib>Matise, Michael P</creatorcontrib><title>Tcf/Lef repressors differentially regulate Shh-Gli target gene activation thresholds to generate progenitor patterning in the developing CNS</title><title>Development (Cambridge)</title><addtitle>Development</addtitle><description>During neural tube development, Shh signaling through Gli transcription factors is necessary to establish five distinct ventral progenitor domains that give rise to unique classes of neurons and glia that arise in specific positions along the dorsoventral axis. These cells are generated from progenitors that display distinct transcription factor gene expression profiles in specific domains in the ventricular zone. However, the molecular genetic mechanisms that control the differential spatiotemporal transcriptional responses of progenitor target genes to graded Shh-Gli signaling remain unclear. The current study demonstrates a role for Tcf/Lef repressor activity in this process. We show that Tcf3 and Tcf7L2 (Tcf4) are required for proper ventral patterning and function by independently regulating two Shh-Gli target genes, Nkx2.2 and Olig2, which are initially induced in a common pool of progenitors that ultimately segregate into unique territories giving rise to distinct progeny. Genetic and functional studies in vivo show that Tcf transcriptional repressors selectively elevate the strength and duration of Gli activity necessary to induce Nkx2.2, but have no effect on Olig2, and thereby contribute to the establishment of their distinct expression domains in cooperation with graded Shh signaling. Together, our data reveal a Shh-Gli-independent transcriptional input that is required to shape the precise spatial and temporal response to extracellular morphogen signaling information during lineage segregation in the CNS.</description><subject>Animals</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Body Patterning - genetics</subject><subject>Body Patterning - physiology</subject><subject>Central Nervous System - cytology</subject><subject>Central Nervous System - embryology</subject><subject>Central Nervous System - metabolism</subject><subject>Chick Embryo</subject><subject>Chromatin Immunoprecipitation</subject><subject>Electroporation</subject><subject>Enhancer Elements, Genetic - genetics</subject><subject>Enhancer Elements, Genetic - physiology</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>In Situ Hybridization</subject><subject>Medicin och hälsovetenskap</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Oligodendrocyte Transcription Factor 2</subject><subject>Polymerase Chain Reaction</subject><subject>Spinal Cord - cytology</subject><subject>Spinal Cord - embryology</subject><subject>Spinal Cord - metabolism</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - metabolism</subject><subject>Transcription Factor 4</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0950-1991</issn><issn>1477-9129</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqFks9u1DAQxiMEotvChQdAviEhpfWfxI4vSGgFBWkFh5az5TjjrMEbB9u7Vd-Bh66X3RZ6QJw8mvl9n2bGU1WvCD4ntKEXA-zOMe-owE-qBWmEqCWh8mm1wLLFNZGSnFSnKX3HGDMuxPPqhBIh2oZ0i-rXtbEXK7AowhwhpRATGpy1EGHKTnt_Wyrj1usM6Gq9ri-9Q1nHETIaYQKkTXY7nV2YUF4Xg3XwQ0I5_K7GvWqOocQuh4hmnTPEyU0jcnseUGkdfJj3meWXqxfVM6t9gpfH96z69vHD9fJTvfp6-Xn5flWblrNcW0LannLQnWHAB9JgbEEyQ3RfMlQIQnRDoWv7hllMKce4bzrNsTW2M8Kws6o--KYbmLe9mqPb6HirgnbqmPpRIlBtQ6UghZf_5Mt4wx_RvZBQhllphBbtu4O2ABsYTFlr1P6xxaPK5NZqDDvFSEsl5cXgzdEghp9bSFltXDLgvZ4gbJOSmDLeMvx_susYxpwQWci3B9LEkFIE-9APwWp_U6p8jDrcVIFf_z3BA3p_ROwOWULM0Q</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>Wang, Hui</creator><creator>Lei, Qiubo</creator><creator>Oosterveen, Tony</creator><creator>Ericson, Johan</creator><creator>Matise, Michael P</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>7TK</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>20110901</creationdate><title>Tcf/Lef repressors differentially regulate Shh-Gli target gene activation thresholds to generate progenitor patterning in the developing CNS</title><author>Wang, Hui ; Lei, Qiubo ; Oosterveen, Tony ; Ericson, Johan ; Matise, Michael P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c563t-f115b26ea8c3e6d1400fe93c1ab8c327711a42e85b43f022600b48a60fcf8c7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Body Patterning - genetics</topic><topic>Body Patterning - physiology</topic><topic>Central Nervous System - cytology</topic><topic>Central Nervous System - embryology</topic><topic>Central Nervous System - metabolism</topic><topic>Chick Embryo</topic><topic>Chromatin Immunoprecipitation</topic><topic>Electroporation</topic><topic>Enhancer Elements, Genetic - genetics</topic><topic>Enhancer Elements, Genetic - physiology</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>In Situ Hybridization</topic><topic>Medicin och hälsovetenskap</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Oligodendrocyte Transcription Factor 2</topic><topic>Polymerase Chain Reaction</topic><topic>Spinal Cord - cytology</topic><topic>Spinal Cord - embryology</topic><topic>Spinal Cord - metabolism</topic><topic>Stem Cells - cytology</topic><topic>Stem Cells - metabolism</topic><topic>Transcription Factor 4</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Lei, Qiubo</creatorcontrib><creatorcontrib>Oosterveen, Tony</creatorcontrib><creatorcontrib>Ericson, Johan</creatorcontrib><creatorcontrib>Matise, Michael P</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>Neurosciences Abstracts</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>Wang, Hui</au><au>Lei, Qiubo</au><au>Oosterveen, Tony</au><au>Ericson, Johan</au><au>Matise, Michael P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tcf/Lef repressors differentially regulate Shh-Gli target gene activation thresholds to generate progenitor patterning in the developing CNS</atitle><jtitle>Development (Cambridge)</jtitle><addtitle>Development</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>138</volume><issue>17</issue><spage>3711</spage><epage>3721</epage><pages>3711-3721</pages><issn>0950-1991</issn><issn>1477-9129</issn><eissn>1477-9129</eissn><abstract>During neural tube development, Shh signaling through Gli transcription factors is necessary to establish five distinct ventral progenitor domains that give rise to unique classes of neurons and glia that arise in specific positions along the dorsoventral axis. These cells are generated from progenitors that display distinct transcription factor gene expression profiles in specific domains in the ventricular zone. However, the molecular genetic mechanisms that control the differential spatiotemporal transcriptional responses of progenitor target genes to graded Shh-Gli signaling remain unclear. The current study demonstrates a role for Tcf/Lef repressor activity in this process. We show that Tcf3 and Tcf7L2 (Tcf4) are required for proper ventral patterning and function by independently regulating two Shh-Gli target genes, Nkx2.2 and Olig2, which are initially induced in a common pool of progenitors that ultimately segregate into unique territories giving rise to distinct progeny. Genetic and functional studies in vivo show that Tcf transcriptional repressors selectively elevate the strength and duration of Gli activity necessary to induce Nkx2.2, but have no effect on Olig2, and thereby contribute to the establishment of their distinct expression domains in cooperation with graded Shh signaling. Together, our data reveal a Shh-Gli-independent transcriptional input that is required to shape the precise spatial and temporal response to extracellular morphogen signaling information during lineage segregation in the CNS.</abstract><cop>England</cop><pub>Company of Biologists</pub><pmid>21775418</pmid><doi>10.1242/dev.068270</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Body Patterning - genetics Body Patterning - physiology Central Nervous System - cytology Central Nervous System - embryology Central Nervous System - metabolism Chick Embryo Chromatin Immunoprecipitation Electroporation Enhancer Elements, Genetic - genetics Enhancer Elements, Genetic - physiology Homeodomain Proteins - genetics Homeodomain Proteins - metabolism In Situ Hybridization Medicin och hälsovetenskap Mice Mice, Transgenic Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Oligodendrocyte Transcription Factor 2 Polymerase Chain Reaction Spinal Cord - cytology Spinal Cord - embryology Spinal Cord - metabolism Stem Cells - cytology Stem Cells - metabolism Transcription Factor 4 Transcription Factors - genetics Transcription Factors - metabolism |
title | Tcf/Lef repressors differentially regulate Shh-Gli target gene activation thresholds to generate progenitor patterning in the developing CNS |
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