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

Abstract EN

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.