Essential role for cyclin D3 in granulocyte colony-stimulating factor-driven expansion of neutrophil granulocytes.
The proliferation of neutrophil granulocyte lineage is driven largely by granulocyte colony-stimulating factor (G-CSF) acting via the G-CSF receptors. In this study, we show that mice lacking cyclin D3, a component of the core cell cycle machinery, are refractory to stimulation by the G-CSF. Consequently, cyclin D3-null mice display deficient maturation of granulocytes in the bone marrow and have reduced levels of neutrophil granulocytes in their peripheral blood. The mutant mice are unable to mount a normal response to bacterial challenge and succumb to microbial infections. In contrast, the expansion of hematopoietic stem cells and lineage-committed myeloid progenitors proceeds relatively normally in mice lacking cyclin D3, revealing that the requirement for cyclin D3 function operates at later stages of neutrophil development. Importantly, we verified that this requirement is specific to cyclin D3, as mice lacking other G(1) cyclins (D1, D2, E1, or E2) display normal granulocyte counts. Our analyses revealed that in the bone marrow cells of wild-type mice, activation of the G-CSF receptor leads to upregulation of cyclin D3. Collectively, these results demonstrate that cyclin D3 is an essential cell cycle recipient of G-CSF signaling, and they provide a molecular link of how G-CSF-dependent signaling triggers cell proliferation.
Sicinska
Ewa
E
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Lee
Young-Mi
YM
Gits
Judith
J
Shigematsu
Hirokazu
H
Yu
Qunyan
Q
Rebel
Vivienne I
VI
Geng
Yan
Y
Marshall
Christopher J
CJ
Akashi
Koichi
K
Dorfman
David M
DM
Touw
Ivo P
IP
Sicinski
Piotr
P
D000818:Animals; D001424:Bacterial Infections; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D019070:Cell Lineage; D049109:Cell Proliferation; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009503:Neutropenia; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D016213:Cyclins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor