Research Article: Loss of Ercc1 Results in a Time- and Dose-Dependent Reduction of Proliferating Early Hematopoietic Progenitors

Date Published: June 3, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Judith H. E. Verhagen-Oldenampsen, Jurgen R. Haanstra, Paulina M. H. van Strien, Marijke Valkhof, Ivo P. Touw, Marieke von Lindern.

http://doi.org/10.1155/2012/783068

Abstract

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.

Partial Text

The Ercc1/Xpf complex is an endonuclease involved in nucleotide excision repair (NER) and in repair of interstrand crosslinks (ICL) [1, 2]. Mice lacking Ercc1 (Ercc1−/−) suffer from severe premature aging, which shows as small size, ruffled fur, liver polyploidy, and loss of hematopoietic progenitors from bone marrow (BM), resulting in death at 3-4 weeks of age [3–6]. Hypomorphic Ercc1 (Ercc1d/d or Ercc1∗292) mice that harbor 2 C-terminally truncated alleles are also small but they survive longer (~6 months), probably as a result of their residual DNA repair capacity (~4%) [1, 2]. The hypomorphic allele has a 7 amino acid deletion at the C-terminus, which impairs dimerization with Xpf [1].

The Ercc1/Xpf endonuclease complex acts downstream of the Fanconi pathway in ICL repair [1, 2, 12]. The hematopoietic defects in Ercc1-deficient mice are reminiscent of the hematopoietic defect of FA patients [23]. It mostly takes several years before FA patients develop anemia. In most FA mouse models, loss of HSC is only seen when the mice are challenged with Mitomycin C [24, 25]. The fact that most mouse models lacking Fanconi genes fail to display overt BM failure may reflect the time it takes to develop anemia. An important factor in the onset of BM failure and leukemia development may be the level of residual DNA repair activity. We employed Ercc1-deficient mouse models to show progressive loss of the number of hematopoietic stem and progenitor cells dependent on Ercc1 activity. Remaining progenitors were compromised in their in vitro proliferation capacity, which was similarly severe in Ercc1−/−, Ercc1−/d, and Ercc1d/d mice.

The authors have no conflict of interests.

J. H. E. Verhagen-Oldenampsen and J. R. Haanstra contributed equally to this paper. I. P. Touw and M. von Lindern share equal responsibility of this paper.

 

Source:

http://doi.org/10.1155/2012/783068

 

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