Notch-dependent control of myelopoiesis is regulated by fucosylation

Abstract

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.

The Notch signaling pathway: Transcriptional regulation at Notch target genes

“…On the one hand, some in vitro studies show that activated Notch signaling inhibits differentiation of myeloid precursors [147 -149]. This is also supported by a recent work using a conditionally induced null mutation in the FX locus, that results in a myeloproliferative phenotype [150]. FX encodes an essential enzyme in the GDP-fucose synthesis pathway.…”

Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation

“…To evaluate out the potential importance of Notch 1 signaling in pulmonary fibrosis, the effects of deficiency in Notch signaling in FX Ϫ/Ϫ mice without exogenous fucose supplementation was examined. 47 Because Notch signaling is required for normal development, the use of KO animals deficient in this critical function is not feasible for studies to demonstrate its in vivo importance in fibrosis. The availability of the FX Ϫ/Ϫ mouse affords a means to study this because Notch deficiency is only evident if the animals are deprived of fucose in their diet, ie, this is effectively a conditional KO.…”

“…Because fucosylation is essential for Notch function, in the absence of exogenous fucose, Notch signaling is deficient in these animals. 47 The de novo appearance of myofibroblasts and their persistence are key features for progressive fibrotic diseases. 21 Our data showed that after BLM treatment, significantly reduced pulmonary fibrosis in Notch-deficient mice was observed with decreased ␣-SMA expression and collagen deposition, suggesting a reduction in genesis of myofibroblasts.…”

“…To further clarify that Notch1 signaling is also important for FIZZ1 induction of myofibroblast differentiation in vivo with contribution to pulmonary fibrosis, the effects of the FX mutation with its well-studied deficiency in Notch signaling, 47 were investigated. First, to confirm that lung fibroblasts from FX KO mice were deficient in their response to FIZZ1-induced myofibroblast differentiation, in vitro analysis was undertaken using cells isolated from these KO mice.…”

Notch signaling in the brain: In good and bad times

“…The O-fucosyltransferase, Pofut, mutant mice are viable but display T cell deficiency as a result of reduced Notchligand interaction and signaling (Ge and Stanley, 2008;Zhou et al, 2008). Two other reports using a zebrafish and a fucosylation loss of function mouse model, show that neuronal development and neuronal plasticity are affected, likely through impairment in Notch signaling (Song et al, 2010;Yagi et al, 2012).…”