Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors
The endonuclease complex Ercc1/Xpf is involved in interstrand crosslink repair and functions downstream of the Fanconi pathway. Loss of Ercc1 causes hematopoietic defects similar to those seen in Fanconi Anemia. Ercc1−/− mice die 3-4 weeks after birth, which prevents long-term follow up of the hemat...
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| Format: | Article |
| Language: | English |
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Wiley
2012-01-01
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| Series: | Anemia |
| Online Access: | http://dx.doi.org/10.1155/2012/783068 |
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| author | Judith H. E. Verhagen-Oldenampsen Jurgen R. Haanstra Paulina M. H. van Strien Marijke Valkhof Ivo P. Touw Marieke von Lindern |
| author_facet | Judith H. E. Verhagen-Oldenampsen Jurgen R. Haanstra Paulina M. H. van Strien Marijke Valkhof Ivo P. Touw Marieke von Lindern |
| author_sort | Judith H. E. Verhagen-Oldenampsen |
| collection | DOAJ |
| description | The endonuclease complex Ercc1/Xpf is involved in interstrand crosslink repair and functions downstream of the Fanconi pathway. Loss of Ercc1 causes hematopoietic defects similar to those seen in Fanconi Anemia. Ercc1−/− mice die 3-4 weeks after birth, which prevents long-term follow up of the hematopoietic compartment. We used alternative Ercc1 mouse models to examine the effect of low or absent Ercc1 activity on hematopoiesis. Tie2-Cre-driven deletion of a floxed Ercc1 allele was efficient (>80%) in fetal liver hematopoietic cells. Hematopoietic stem and progenitor cells (HSPCs) with a deleted allele were maintained in mice up to 1 year of age when harboring a wt allele, but were progressively outcompeted when the deleted allele was combined with a knockout allele. Mice with a minimal Ercc1 activity expressed by 1 or 2 hypomorphic Ercc1 alleles have an extended life expectancy, which allows analysis of HSPCs at 10 and 20 weeks of age. The HSPC compartment was affected in all Ercc1-deficient models. Actively proliferating multipotent progenitors were most affected as were myeloid and erythroid clonogenic progenitors. In conclusion, lack of Ercc1 results in a severe competitive disadvantage of HSPCs and is most deleterious in proliferating progenitor cells. |
| format | Article |
| id | doaj-art-e097eb68b92c4f35aff5534b3d7bd528 |
| institution | Kabale University |
| issn | 2090-1267 2090-1275 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Anemia |
| spelling | doaj-art-e097eb68b92c4f35aff5534b3d7bd5282025-08-20T03:26:09ZengWileyAnemia2090-12672090-12752012-01-01201210.1155/2012/783068783068Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic ProgenitorsJudith H. E. Verhagen-Oldenampsen0Jurgen R. Haanstra1Paulina M. H. van Strien2Marijke Valkhof3Ivo P. Touw4Marieke von Lindern5Department of Hematology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The NetherlandsDepartment of Hematology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The NetherlandsDepartment of Hematology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The NetherlandsDepartment of Hematology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The NetherlandsDepartment of Hematology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The NetherlandsDepartment of Hematology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The NetherlandsThe endonuclease complex Ercc1/Xpf is involved in interstrand crosslink repair and functions downstream of the Fanconi pathway. Loss of Ercc1 causes hematopoietic defects similar to those seen in Fanconi Anemia. Ercc1−/− mice die 3-4 weeks after birth, which prevents long-term follow up of the hematopoietic compartment. We used alternative Ercc1 mouse models to examine the effect of low or absent Ercc1 activity on hematopoiesis. Tie2-Cre-driven deletion of a floxed Ercc1 allele was efficient (>80%) in fetal liver hematopoietic cells. Hematopoietic stem and progenitor cells (HSPCs) with a deleted allele were maintained in mice up to 1 year of age when harboring a wt allele, but were progressively outcompeted when the deleted allele was combined with a knockout allele. Mice with a minimal Ercc1 activity expressed by 1 or 2 hypomorphic Ercc1 alleles have an extended life expectancy, which allows analysis of HSPCs at 10 and 20 weeks of age. The HSPC compartment was affected in all Ercc1-deficient models. Actively proliferating multipotent progenitors were most affected as were myeloid and erythroid clonogenic progenitors. In conclusion, lack of Ercc1 results in a severe competitive disadvantage of HSPCs and is most deleterious in proliferating progenitor cells.http://dx.doi.org/10.1155/2012/783068 |
| spellingShingle | Judith H. E. Verhagen-Oldenampsen Jurgen R. Haanstra Paulina M. H. van Strien Marijke Valkhof Ivo P. Touw Marieke von Lindern Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors Anemia |
| title | Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors |
| title_full | Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors |
| title_fullStr | Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors |
| title_full_unstemmed | Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors |
| title_short | Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors |
| title_sort | loss of ercc1 results in a time and dose dependent reduction of proliferating early hematopoietic progenitors |
| url | http://dx.doi.org/10.1155/2012/783068 |
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