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L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development
Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung...
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Published in: | Neurogastroenterology and motility 2011-11, Vol.23 (11), p.e510-e522 |
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creator | Wallace, A. S. Tan, M. X. Schachner, M. Anderson, R. B. |
description | Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung’s disease. The high degree of phenotypic variability reported in Hirschsprung’s disease suggests the involvement of modifier genes.
Methods We used a two‐locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5+ enteric neurons and Sox10+ neural crest‐derived cells in wholemount preparations of embryonic gut.
Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et‐3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest‐derived cells was significantly delayed in L1cam−/y; Et‐3−/− and L1cam−/y;Ednrbsl/sl embryos.
Conclusions & Inferences We have identified the X‐linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung’s disease. |
doi_str_mv | 10.1111/j.1365-2982.2011.01692.x |
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Methods We used a two‐locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5+ enteric neurons and Sox10+ neural crest‐derived cells in wholemount preparations of embryonic gut.
Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et‐3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest‐derived cells was significantly delayed in L1cam−/y; Et‐3−/− and L1cam−/y;Ednrbsl/sl embryos.
Conclusions & Inferences We have identified the X‐linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung’s disease.</description><identifier>ISSN: 1350-1925</identifier><identifier>EISSN: 1365-2982</identifier><identifier>DOI: 10.1111/j.1365-2982.2011.01692.x</identifier><identifier>PMID: 21395909</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Apoptosis - physiology ; Cell migration ; Cell Movement - physiology ; Cell Proliferation ; Colonization ; Complementation ; development ; Digestive tract ; Embryos ; Endothelin 3 ; Endothelins - genetics ; Endothelins - metabolism ; Enteric nervous system ; Enteric Nervous System - abnormalities ; Enteric Nervous System - embryology ; Foregut ; Ganglia ; Genes, Modifier ; Genes, X-Linked ; Genetic Complementation Test ; haploinsufficiency ; Hindgut ; Hirschsprung Disease - embryology ; Hirschsprung Disease - genetics ; Hirschsprung Disease - metabolism ; Hirschsprung's disease ; Humans ; Immunohistochemistry ; Intestines - embryology ; Intestines - innervation ; Mice ; Mice, Knockout ; Midgut ; Mutation ; Neural Cell Adhesion Molecule L1 - genetics ; Neural Cell Adhesion Molecule L1 - metabolism ; Neural crest ; Neurons ; Receptors, Endothelin - genetics ; Receptors, Endothelin - metabolism ; Signal transduction ; Signal Transduction - physiology ; X chromosome</subject><ispartof>Neurogastroenterology and motility, 2011-11, Vol.23 (11), p.e510-e522</ispartof><rights>2011 Blackwell Publishing Ltd</rights><rights>2011 Blackwell Publishing Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3512-96db40c68978e8fefce1bf56052b48469b47ee9c75394bb9d5b85773bda7d97d3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21395909$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wallace, A. S.</creatorcontrib><creatorcontrib>Tan, M. X.</creatorcontrib><creatorcontrib>Schachner, M.</creatorcontrib><creatorcontrib>Anderson, R. B.</creatorcontrib><title>L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development</title><title>Neurogastroenterology and motility</title><addtitle>Neurogastroenterol Motil</addtitle><description>Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung’s disease. The high degree of phenotypic variability reported in Hirschsprung’s disease suggests the involvement of modifier genes.
Methods We used a two‐locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5+ enteric neurons and Sox10+ neural crest‐derived cells in wholemount preparations of embryonic gut.
Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et‐3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest‐derived cells was significantly delayed in L1cam−/y; Et‐3−/− and L1cam−/y;Ednrbsl/sl embryos.
Conclusions & Inferences We have identified the X‐linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung’s disease.</description><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Cell migration</subject><subject>Cell Movement - physiology</subject><subject>Cell Proliferation</subject><subject>Colonization</subject><subject>Complementation</subject><subject>development</subject><subject>Digestive tract</subject><subject>Embryos</subject><subject>Endothelin 3</subject><subject>Endothelins - genetics</subject><subject>Endothelins - metabolism</subject><subject>Enteric nervous system</subject><subject>Enteric Nervous System - abnormalities</subject><subject>Enteric Nervous System - embryology</subject><subject>Foregut</subject><subject>Ganglia</subject><subject>Genes, Modifier</subject><subject>Genes, X-Linked</subject><subject>Genetic Complementation Test</subject><subject>haploinsufficiency</subject><subject>Hindgut</subject><subject>Hirschsprung Disease - embryology</subject><subject>Hirschsprung Disease - genetics</subject><subject>Hirschsprung Disease - metabolism</subject><subject>Hirschsprung's disease</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Intestines - embryology</subject><subject>Intestines - innervation</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Midgut</subject><subject>Mutation</subject><subject>Neural Cell Adhesion Molecule L1 - genetics</subject><subject>Neural Cell Adhesion Molecule L1 - metabolism</subject><subject>Neural crest</subject><subject>Neurons</subject><subject>Receptors, Endothelin - genetics</subject><subject>Receptors, Endothelin - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - physiology</subject><subject>X chromosome</subject><issn>1350-1925</issn><issn>1365-2982</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqFkctOwzAQRS0Eorx-AXnHKsF2YidesEAVL6nABtaWHU_aVHFS7JS2f4_Do1tGI8217tXImoMQpiSlsa6XKc0ET5gsWcoIpSmhQrJ0e4BO9sbhqDlJqGR8gk5DWBJCBMvFMZowmkkuiTxB2xmttMO6GgLWsbHrbVM34PEcOsB177EDZ8AH3Nd4WACGzvZxtk2HQzPvdBvVHK_0sNjoHbZrPz6hG8A3Fe7Af_brgMMuDOCwhU9o-5WL9jk6qnUb4OJ3nqH3-7u36WMye314mt7OkirjlCVSWJOTSpSyKKGsoa6AmpoLwpnJy1xIkxcAsip4JnNjpOWm5EWRGasLKwubnaGrn70r33-sIQzKNaGCttUdxJ8pGe_Jy5wV_ydJJgQjJY_Jy9_k2jiwauUbp_1O_Z01Bm5-Apumhd3ep0SN-NRSjZTUSEmN-NQ3PrVVL8-vo8q-AAdMj14</recordid><startdate>201111</startdate><enddate>201111</enddate><creator>Wallace, A. S.</creator><creator>Tan, M. X.</creator><creator>Schachner, M.</creator><creator>Anderson, R. B.</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7TK</scope></search><sort><creationdate>201111</creationdate><title>L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development</title><author>Wallace, A. S. ; Tan, M. X. ; Schachner, M. ; Anderson, R. B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3512-96db40c68978e8fefce1bf56052b48469b47ee9c75394bb9d5b85773bda7d97d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Cell migration</topic><topic>Cell Movement - physiology</topic><topic>Cell Proliferation</topic><topic>Colonization</topic><topic>Complementation</topic><topic>development</topic><topic>Digestive tract</topic><topic>Embryos</topic><topic>Endothelin 3</topic><topic>Endothelins - genetics</topic><topic>Endothelins - metabolism</topic><topic>Enteric nervous system</topic><topic>Enteric Nervous System - abnormalities</topic><topic>Enteric Nervous System - embryology</topic><topic>Foregut</topic><topic>Ganglia</topic><topic>Genes, Modifier</topic><topic>Genes, X-Linked</topic><topic>Genetic Complementation Test</topic><topic>haploinsufficiency</topic><topic>Hindgut</topic><topic>Hirschsprung Disease - embryology</topic><topic>Hirschsprung Disease - genetics</topic><topic>Hirschsprung Disease - metabolism</topic><topic>Hirschsprung's disease</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Intestines - embryology</topic><topic>Intestines - innervation</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Midgut</topic><topic>Mutation</topic><topic>Neural Cell Adhesion Molecule L1 - genetics</topic><topic>Neural Cell Adhesion Molecule L1 - metabolism</topic><topic>Neural crest</topic><topic>Neurons</topic><topic>Receptors, Endothelin - genetics</topic><topic>Receptors, Endothelin - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - physiology</topic><topic>X chromosome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wallace, A. S.</creatorcontrib><creatorcontrib>Tan, M. X.</creatorcontrib><creatorcontrib>Schachner, M.</creatorcontrib><creatorcontrib>Anderson, R. B.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Neurogastroenterology and motility</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wallace, A. S.</au><au>Tan, M. X.</au><au>Schachner, M.</au><au>Anderson, R. B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development</atitle><jtitle>Neurogastroenterology and motility</jtitle><addtitle>Neurogastroenterol Motil</addtitle><date>2011-11</date><risdate>2011</risdate><volume>23</volume><issue>11</issue><spage>e510</spage><epage>e522</epage><pages>e510-e522</pages><issn>1350-1925</issn><eissn>1365-2982</eissn><abstract>Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung’s disease. The high degree of phenotypic variability reported in Hirschsprung’s disease suggests the involvement of modifier genes.
Methods We used a two‐locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5+ enteric neurons and Sox10+ neural crest‐derived cells in wholemount preparations of embryonic gut.
Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et‐3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest‐derived cells was significantly delayed in L1cam−/y; Et‐3−/− and L1cam−/y;Ednrbsl/sl embryos.
Conclusions & Inferences We have identified the X‐linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung’s disease.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21395909</pmid><doi>10.1111/j.1365-2982.2011.01692.x</doi><tpages>13</tpages></addata></record> |
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subjects | Animals Apoptosis - physiology Cell migration Cell Movement - physiology Cell Proliferation Colonization Complementation development Digestive tract Embryos Endothelin 3 Endothelins - genetics Endothelins - metabolism Enteric nervous system Enteric Nervous System - abnormalities Enteric Nervous System - embryology Foregut Ganglia Genes, Modifier Genes, X-Linked Genetic Complementation Test haploinsufficiency Hindgut Hirschsprung Disease - embryology Hirschsprung Disease - genetics Hirschsprung Disease - metabolism Hirschsprung's disease Humans Immunohistochemistry Intestines - embryology Intestines - innervation Mice Mice, Knockout Midgut Mutation Neural Cell Adhesion Molecule L1 - genetics Neural Cell Adhesion Molecule L1 - metabolism Neural crest Neurons Receptors, Endothelin - genetics Receptors, Endothelin - metabolism Signal transduction Signal Transduction - physiology X chromosome |
title | L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development |
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