Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis.
Expression of the Src-family kinases--Src, Hck, and Fgr--increases dramatically during myeloid cell development. Src-deficient mice exhibit functional abnormalities in only one myeloid cell type, the osteoclast, resulting in impaired bone remodeling and osteopetrosis, while hck-/- or fgr-/- mice have few and subtle myeloid cell deficiencies. To determine whether these limited phenotypes are due to the coexpression of multiple Src-family kinases with overlapping functions, we have intercrossed src-/- mice to hck-/- and fgr-/- mutants to produce double mutants. Two thirds of hck-/- src-/- double mutants die at birth; surviving animals develop a severe form of osteopetrosis, resulting in extreme levels of splenic extramedullary hematopoiesis, anemia, and leukopenia. These hematopoietic defects are caused by abnormalities in the bone marrow environment because hck-/- src-/- mutant stem cells reconstitute a normal hematopoietic system in irradiated wild-type mice. In contrast, fgr-/- src-/- double mutants have no defects beyond those observed in src-/- animals. Cultured normal murine osteoclasts express abundant amounts of Src, Hck, and Fgr and Hck levels are increased in src-/- osteoclasts. These observations suggest that Hck and Src serve partially overlapping functions in osteoclasts and that the expression of Hck in src-/- osteoclasts ameliorates their functional defects.
Lowell
C A
CA
Department of Microbiology and Immunology, University of California, San Francisco, USA.
Niwa
M
M
Soriano
P
P
Varmus
H E
HE
D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001862:Bone Resorption; D002478:Cells, Cultured; D003433:Crosses, Genetic; D005260:Female; D006411:Hematopoiesis, Extramedullary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D010022:Osteopetrosis / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051572:Proto-Oncogene Proteins c-hck; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000473:pathology; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; D016392:Proto-Oncogene Proteins pp60(c-src); C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases