title: Heterozygous kit mutants with little or no apparent anemia exhibit large defects in overall hematopoietic stem cell function.
abstract: OBJECTIVE
  The evolutionarily conserved Kit receptor is vital for function of hematopoietic stem cells (HSC). Kit(W-41) (W-41) and Kit(W-42) (W-42) are single residue changes in the KIT intracellular phosphotransferase domain, while Kit(W-v) (W-v) is a single residue change in the ATP binding domain. This study tests how each mutation affects HSC function.
  
  
  METHODS
  Cells in mutant and C57BL/6J(+/+) blood and marrow were compared. Overall HSC function was measured by competitive repopulation. Functions of specific progenitor populations were tested with stage-specific competitive repopulation and standard colony-forming unit assays.
  
  
  RESULTS
  Bone marrow cells from these Kit mutants are severely defective at reconstituting peripheral blood lineages and bone marrow of irradiated recipients, when compared to +/+ control marrow. These defects increased with time. Marrow from W-41/+ and W-v/+ functions similarly but better than marrow from W-41/W-41 and W-42/+, to repopulate the erythroid and lymphoid lineages. Long-term (LT) and short-term (ST) HSC from W-v/+, W-41/W-41, and W-42/+ are more defective at reconstituting bone marrow than LT- and ST-HSC from W-41/+ and +/+. Common myeloid progenitor (CMP) cells from W-42/+ and W-41/W-41 are more defective at producing spleen colonies than CMP from W-v/+ and W-41/+.
  
  
  CONCLUSIONS
  Heterozygous Kit mutants with little or no apparent anemia exhibit surprisingly large defects in overall HSC function. Multiplying the fractional defects in LT-HSC, ST-HSC, and CMP can account for overall effects of W-v/+, but does not completely account for the defects observed with W-41/+, W-42/+, and W-41/W-41.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Yashoda
authors.initials: Y
authors.lastname: Sharma
authors.forename: Clinton M
authors.initials: CM
authors.lastname: Astle
authors.forename: David E
authors.initials: DE
authors.lastname: Harrison
mesh_terms: D000740:Anemia / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D001792:Blood Platelets / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000528:radiation effects; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology / Q000528:radiation effects; D003114:Colony-Forming Units Assay / Q000379:methods; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000276:immunology
chemical_list: D019009:Proto-Oncogene Proteins c-kit