Truncation of c-fes via gene targeting results in embryonic lethality and hyperproliferation of hematopoietic cells.
The c-fes protooncogene encodes a nonreceptor tyrosine kinase (Fes) implicated in cytokine receptor signal transduction, granulocyte survival, and myeloid differentiation. To study the role of c-fes during myelopoiesis, we generated embryonic stem (ES) cells with a targeted disruption of the c-fes locus. Targeted mutagenesis deletes the C-terminal SH2 and tyrosine kinase domains of c-fes (referred to as c-fes(Delta c/Delta c)). We demonstrate that the c-fes(Delta c/Delta c) allele results in a truncated Fes protein that retains the N-terminal oligomerization domain, but lacks both the SH2 and the tyrosine kinase domain. In vitro differentiation of c-fes(Delta c/Delta c) ES cells results in hyperproliferation of an early myeloid cell. Generation of c-fes(Delta c/Delta c) mutant chimeric mice causes lethality by E13.5 with embryos exhibiting pleiotropic defects, the most striking being cardiovascular abnormalities. These results establish that c-fes is an important regulator of myeloid cell proliferation and embryonic development.
Hackenmiller
Renee
R
Committee on Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Simon
M Celeste
MC
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D020964:Embryo Loss / Q000235:genetics*; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D018390:Gene Targeting; D005804:Genes, Lethal / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed / Q000235:genetics*; D023461:Myeloid Progenitor Cells / Q000166:cytology; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051578:Proto-Oncogene Proteins c-fes; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; C496645:FES protein, human; C496646:Fes protein, mouse; D051578:Proto-Oncogene Proteins c-fes