A critical function for B-Raf at multiple stages of myelopoiesis.
Raf kinases play an integral role in the classic mitogen-activated protein (MAP) kinase (Raf/MEK/extracellular signal-related kinase [ERK]) intracellular signaling cascade, but their role in specific developmental processes is largely unknown. Using a genetic approach, we have identified a role for B-Raf during hematopoietic progenitor cell development and during megakaryocytopoiesis. Fetal liver and in vitro embryonic stem (ES) cell-derived myeloid progenitor development is quantitatively impaired in the absence of B-Raf. Biochemical data suggest that this phenotype is due to the loss of a normally occurring rise in B-Raf expression and associated ERK1/2 activation during hematopoietic progenitor cell formation. However, the presence of B-raf-/- ES cell-derived myeloid progenitors in the bone marrow of adult chimeric mice indicates the lack of an obligate cell-autonomous requirement for B-Raf in myeloid progenitor development. The lack of B-Raf also impairs megakaryocytopoiesis. Thrombopoietin (Tpo)-induced in vitro expansion of ES cell-derived megakaryocyte-lineage cells fails to occur in the absence of B-Raf. Moreover, this quantitative in vitro defect in megakaryocyte-lineage expansion is mirrored by chimeric mice data that show reduced B-raf-/- genotype contribution in megakaryocytes relative to its contribution in myeloid progenitors. Together, these data suggest that B-Raf plays a cell-autonomous role in megakaryocytopoiesis and a permissive role in myeloid progenitor development.
Kamata
Tamihiro
T
Department of Laboratory Medicine, University of California, San Francisco, 513 Parnassus Ave, Room S-577, San Francisco, CA 94143-0100, USA.
Kang
Jing
J
Lee
Tzong-Hae
TH
Wojnowski
Leszek
L
Pritchard
Catrin A
CA
Leavitt
Andrew D
AD
D000818:Animals; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis; D048493:Proto-Oncogene Proteins B-raf / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells; D034061:Thrombopoiesis
C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf