Notch-dependent control of myelopoiesis is regulated by fucosylation.
Cell-cell contact-dependent mechanisms that modulate proliferation and/or differentiation in the context of hematopoiesis include mechanisms characteristic of the interactions between members of the Notch family of signal transduction molecules and their ligands. Whereas Notch family members and their ligands clearly modulate T lymphopoietic decisions, evidence for their participation in modulating myelopoiesis is much less clear, and roles for posttranslational control of Notch-dependent signal transduction in myelopoiesis are unexplored. We report here that a myeloproliferative phenotype in FX(-/-) mice, which are conditionally deficient in cellular fucosylation, is consequent to loss of Notch-dependent signal transduction on myeloid progenitor cells. In the context of a wild-type fucosylation phenotype, we find that the Notch ligands suppress myeloid differentiation of progenitor cells and enhance expression of Notch target genes. By contrast, fucosylation-deficient myeloid progenitors are insensitive to the suppressive effects of Notch ligands on myelopoiesis, do not transcribe Notch1 target genes when cocultured with Notch ligands, and have lost the wild-type Notch ligand-binding phenotype. Considered together, these observations indicate that Notch-dependent signaling controls myelopoiesis in vivo and in vitro and identifies a requirement for Notch fucosylation in the expression of Notch ligand binding activity and Notch signaling efficiency in myeloid progenitors.
Zhou
Lan
L
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. lan.zhou@case.edu
Li
Lebing Wei
LW
Yan
Quanjian
Q
Petryniak
Bronislawa
B
Man
Yunfang
Y
Su
Charles
C
Shim
Jeongsup
J
Chervin
Stephanie
S
Lowe
John B
JB
D000818:Animals; D002454:Cell Differentiation; D005643:Fucose / Q000378:metabolism*; D006031:Glycosylation; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells; D038042:Myelopoiesis; D051881:Receptor, Notch1 / Q000502:physiology*
D051881:Receptor, Notch1; D005643:Fucose