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The quantitative trait gene latexin influences the size of the hematopoietic stem cell population in mice

Nature Genetics volume 39, pages 178–188 (2007)Cite this article

Abstract

We mapped quantitative trait loci that accounted for the variation in hematopoietic stem cell (HSC) numbers between young adult C57BL/6 (B6) and DBA/2 (D2) mice. In reciprocal chromosome 3 congenic mice, introgressed D2 alleles increased HSC numbers owing to enhanced proliferation and self-renewal and reduced apoptosis, whereas B6 alleles had the opposite effects. Using oligonucleotide arrays, real-time PCR and protein blots, we identified latexin (Lxn), a gene whose differential transcription and expression was associated with the allelic differences. Expression was inversely correlated with the number of HSCs; therefore, ectopic expression of Lxn using a retroviral vector decreased stem cell population size. We identified clusters of SNPs upstream of the Lxn transcriptional start site, at least two of which are associated with potential binding sites for transcription factors regulating stem cells. Thus, promoter polymorphisms between the B6 and D2 alleles may affect Lxn gene expression and consequently influence the population size of hematopoietic stem cells.

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Figure 1: Linkage analysis and Chr3 congenic mouse strains.
Figure 2: HSC frequency in Chr3 congenic mice.
Figure 3: Replication, self-renewal and apoptosis analysis of Chr3 congenic HSCs.
Figure 4: Differential expression of Lxn in congenic, B6 and D2 mice.
Figure 5: QTL regulating Lxn expression.
Figure 6: Overexpression of Lxn decreases the number of HSCs.
Figure 7: SNPs in Lxn gene regulatory regions of B6 and D2 alleles.

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Acknowledgements

We acknowledge the flow cytometric expertise of B. Grimes, the technical assistance of C. Swiderski and the editorial assistance of P. Thomason. This work was supported by the US National Institutes of Health (grants AG020917, AG024950 and AG022859).

Author information

Authors and Affiliations

  1. Departments of Internal Medicine and Physiology, University of Kentucky, Lexington, 40536, Kentucky, USA

    Ying Liang & Gary Van Zant

  2. Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA

    Michael Jansen & Bruce Aronow

  3. Division of Experimental Hematology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA

    Michael Jansen & Hartmut Geiger

Authors
  1. Ying Liang
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Contributions

Y.L. performed the majority of the experimental work in the course of her Ph.D. dissertation project, contributed to the design of the study and contributed to the writing of this paper. M.J. and B.A. contributed to the Lxn promoter SNP analyses and identification of potential regulatory sites. H.G. generated the congenic strains, carried out initial phenotyping of the congenics and contributed to the writing of this paper. G.V.Z. was largely responsible for the design of the study and writing of this paper.

Corresponding author

Correspondence to Gary Van Zant.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

CAFC day 35 numbers in B6, D2 nad BXD recombinant inbred strains. (PDF 44 kb)

Supplementary Table 2

Hematopoietic progenitor cells (HPCs) and peripheral blood cell counts in Chr3 congenic and background mouse strains. (PDF 54 kb)

Supplementary Table 3

Genes differentially expressed in LSK cells between B.D Chr3 congenic and B6 strains. (PDF 80 kb)

Supplementary Table 4

Genes differentially expressed in LSK cells between D.B Chr3 and D2 strains. (PDF 75 kb)

Supplementary Table 5

Confirmation of SNPs between B6 and D2 alleles in the regulatory region of Lxn. (PDF 60 kb)

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Liang, Y., Jansen, M., Aronow, B. et al. The quantitative trait gene latexin influences the size of the hematopoietic stem cell population in mice. Nat Genet 39, 178–188 (2007). https://doi.org/10.1038/ng1938

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