L1cam acts as a modifier gene during enteric nervous system development
The enteric nervous system is derived from neural crest cells that migrate from the caudal hindbrain and colonise the gut. Failure of neural crest cells to fully colonise the gut results in an “aganglionic zone” that lacks a functional enteric nervous system over a variable length of the distal bowe...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2010-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996110002615 |
| _version_ | 1818352338124931072 |
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| author | Adam S. Wallace Claudia Schmidt Melitta Schachner Michael Wegner Richard B. Anderson |
| author_facet | Adam S. Wallace Claudia Schmidt Melitta Schachner Michael Wegner Richard B. Anderson |
| author_sort | Adam S. Wallace |
| collection | DOAJ |
| description | The enteric nervous system is derived from neural crest cells that migrate from the caudal hindbrain and colonise the gut. Failure of neural crest cells to fully colonise the gut results in an “aganglionic zone” that lacks a functional enteric nervous system over a variable length of the distal bowel, a condition in human infants known as Hirschsprung's disease. The variability observed in the penetrance and severity of Hirschsprung's disease suggests a role for modifier genes. Clinical studies have identified a population of Hirschsprung's patients with mutations in L1CAM that also have a common polymorphism in RET, suggesting a possible interaction between L1CAM and RET. Therefore, we examined whether L1cam could interact with Ret, its ligand Gdnf, and a known transcriptional activator of Ret, Sox10. Using a two-locus complementation approach, we show that loss of L1cam in conjunction with a heterozygous loss of Ret or Gdnf did not result in aganglionosis. However, L1cam did interact with Sox10 to significantly increase the incidence of aganglionosis. We show that an interaction between L1cam and Sox10 significantly perturbs neural crest migration within the developing gut, and that neural crest cells undergo excessive cell death prior to gut entry. Finally, we show that Sox10 can regulate the expression of L1cam. Thus, L1cam can act as a modifier gene for the HSCR associated gene, Sox10, and is likely to play a role in the etiology of Hirschsprung's disease. |
| first_indexed | 2024-12-13T18:52:03Z |
| format | Article |
| id | doaj.art-50b4064cfe684f0a82361d35b5df0b83 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:52:03Z |
| publishDate | 2010-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-50b4064cfe684f0a82361d35b5df0b832022-12-21T23:34:55ZengElsevierNeurobiology of Disease1095-953X2010-12-01403622633L1cam acts as a modifier gene during enteric nervous system developmentAdam S. Wallace0Claudia Schmidt1Melitta Schachner2Michael Wegner3Richard B. Anderson4Department of Anatomy and Cell Biology, University of Melbourne, 3010, AustraliaInstitut fur Biochemie, Universitat Erlangen-Nurnberg, D-91054, GermanyZentrum fur Molekulare Neurobiologie, University of Hamburg, 20246, GermanyInstitut fur Biochemie, Universitat Erlangen-Nurnberg, D-91054, GermanyDepartment of Anatomy and Cell Biology, University of Melbourne, 3010, Australia; Corresponding author. Department of Anatomy and Cell Biology, University of Melbourne, Parkville 3010, Australia. Fax: +61 3 9347 5219.The enteric nervous system is derived from neural crest cells that migrate from the caudal hindbrain and colonise the gut. Failure of neural crest cells to fully colonise the gut results in an “aganglionic zone” that lacks a functional enteric nervous system over a variable length of the distal bowel, a condition in human infants known as Hirschsprung's disease. The variability observed in the penetrance and severity of Hirschsprung's disease suggests a role for modifier genes. Clinical studies have identified a population of Hirschsprung's patients with mutations in L1CAM that also have a common polymorphism in RET, suggesting a possible interaction between L1CAM and RET. Therefore, we examined whether L1cam could interact with Ret, its ligand Gdnf, and a known transcriptional activator of Ret, Sox10. Using a two-locus complementation approach, we show that loss of L1cam in conjunction with a heterozygous loss of Ret or Gdnf did not result in aganglionosis. However, L1cam did interact with Sox10 to significantly increase the incidence of aganglionosis. We show that an interaction between L1cam and Sox10 significantly perturbs neural crest migration within the developing gut, and that neural crest cells undergo excessive cell death prior to gut entry. Finally, we show that Sox10 can regulate the expression of L1cam. Thus, L1cam can act as a modifier gene for the HSCR associated gene, Sox10, and is likely to play a role in the etiology of Hirschsprung's disease.http://www.sciencedirect.com/science/article/pii/S0969996110002615Hirschsprung's diseaseNeural crestCell migrationEnteric nervous systemDevelopment |
| spellingShingle | Adam S. Wallace Claudia Schmidt Melitta Schachner Michael Wegner Richard B. Anderson L1cam acts as a modifier gene during enteric nervous system development Neurobiology of Disease Hirschsprung's disease Neural crest Cell migration Enteric nervous system Development |
| title | L1cam acts as a modifier gene during enteric nervous system development |
| title_full | L1cam acts as a modifier gene during enteric nervous system development |
| title_fullStr | L1cam acts as a modifier gene during enteric nervous system development |
| title_full_unstemmed | L1cam acts as a modifier gene during enteric nervous system development |
| title_short | L1cam acts as a modifier gene during enteric nervous system development |
| title_sort | l1cam acts as a modifier gene during enteric nervous system development |
| topic | Hirschsprung's disease Neural crest Cell migration Enteric nervous system Development |
| url | http://www.sciencedirect.com/science/article/pii/S0969996110002615 |
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