A genetic determinant that specifically regulates the frequency of hematopoietic stem cells.
The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. We screened for genetic polymorphisms that were linked to differences between mouse strains in the numbers of long-term reconstituting HSCs or restricted progenitors in the bone marrow. AKR/J mice had significantly higher frequencies and numbers of both HSCs and restricted progenitors in their bone marrow than C57BL/Ka-Thy-1.1 mice. The C57BL/Ka-Thy-1.1 alleles were partially dominant. A locus on chromosome 17, including the H-2 complex, was significantly linked to the frequency of long-term self-renewing HSCs but showed no evidence of linkage to the frequency of restricted progenitors. Conversely, a chromosome 1 locus exhibited suggestive linkage to restricted progenitor frequencies but was not linked to HSC frequency. This demonstrates that there are distinct genetic determinants of the frequencies of HSCs and restricted progenitors in vivo. The AKR/J chromosome 17 locus was not sufficient to increase HSC frequencies when bred onto a C57BL background. This suggests that to affect HSC frequencies, the product(s) of this locus likely depend on interactions with unlinked modifying loci.
Morrison
Sean J
SJ
Howard Hughes Medical Institute and Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Qian
Dalong
D
Jerabek
Libuse
L
Thiel
Bonnie A
BA
Park
In-Kyung
IK
Ford
Preston S
PS
Kiel
Mark J
MJ
Schork
Nicholas J
NJ
Weissman
Irving L
IL
Clarke
Michael F
MF
D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005819:Genetic Markers / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D007958:Leukocyte Count; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D011110:Polymorphism, Genetic / Q000276:immunology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D013045:Species Specificity; D018800:Thy-1 Antigens / Q000096:biosynthesis
D000950:Antigens, Ly; D005819:Genetic Markers; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D018800:Thy-1 Antigens; D019009:Proto-Oncogene Proteins c-kit