Table 1.
Summary of the effects of Wnt pathway perturbations on hematopoietic development.
| Gene (perturbed) | Wnt up/down-regulated? | Model System | Phenotype | Tissue | Time | Notes | Reference | ||
|---|---|---|---|---|---|---|---|---|---|
| Human | Extracellular | Exogenous DKK1 | Down | Human (in vitro ESC differentiation) | Decrease in HSPCs | N/A | d0 - endpoint | Decrease in CD34/CD45+ cells, decrease in CFCs | Woll et al. Blood 2008 |
| Exogenous Wnt1 | Up | Human (in vitro ESC differentiation) | Increase in HSPCs | N/A | d0 - endpoint | Increase in CD34/CD45+ cells, decrease in CFCs | Woll et al. Blood 2008 | ||
| Exogenous WNT3A | Up | Human (in vitro ESC differentiation) | Increase in HSPCs | N/A | d0 - 4? | Increase in CFCs | Gertow et al. Stem Cell Reports 2013 | ||
| Exogenous Wnt3a | Up | Human (in vitro iPSC differentiation) | Increase in HSPCs | N/A | d0 - endpoint | Wnt3a protein; Increase in HSC markers, EM-CFC colonies in CFC assay | Wang and Nakayama, Stem Cell Research 2009 | ||
| Exogenous Wnt3a | Up | Human (in vitro ESC differentiation) | Increase in HSPCs | N/A | d0 | Increased HSPCs as measured by CFC assay | Wang and Nakayama, Stem Cell Research 2009 | ||
| Inhibition of Wnt secretion | Down | Human (in vitro ESC differentiation) | Decrease in HSPCs | N/A | d2-3 | IWP2; Decreased HSCs as measured by lack of T cell potential | Sturgeon et al. Nature Biotechnology 2014 | ||
| Cytoplasmic | GSK3B inhibition | Up | Human (in vitro) | Increase in HSPCs, lack of primitive blood | N/A | d2-3 | CHIR99021; Increased HSCs as measured by T cell potential | Sturgeon et al. Nature Biotechnology 2014 | |
| GSK3B inhibition | Up | Human (in vitro) | Increased HSPCs | N/A | d0-1 | CHIR99021; increased CFU-mix colonies, increased %CD34+/CD43- | Kitajima et al. Experimental Hematology 2016 | ||
| Mouse | Extracellular | Wnt2 | Down | Mouse (in vitro ESC differentiation) | Increased HSPCs | N/A | N/A | Wnt2 KO, increased BL-CFC colonies in EB differentiation | Wang et al. Journal of Biological Chemistry 2007 |
| Wnt3a | Down | Mouse (in vivo) | Decrease in LSK cells | Fetal liver | E12.5 | Wnt3a KO, Decreased long term reconstitution capacity - secondary recpients had poor engraftment; decreased self-renewal; reduction of myeloid progenitors | Luis et al. Blood 2009 | ||
| Exogenous Wnt3a | Up | Mouse (ex vivo) | Increase in EMPs | Yolk sac explants | N/A | CFC assay | Frame et al. Stem Cells 2016 | ||
| Increased Wnt3a (high, exogenous) | Up | Mouse (ex vivo) | Decrease in T cells, increase in B cells | Fetal liver on OP9 stroma | N/A | Coculture assay, and fetal liver LSK+ cells transplanted into adult mice | Famili et al. Cell Death and Disease 2015 | ||
| Increased Wnt3a (physiological) | Up | Mouse (ex vivo) | Acceleration of T cell development | Fetal liver on OP9 stroma | N/A | Coculture assay, and fetal liver LSK+ cells transplanted into adult mice | Famili et al. Cell Death and Disease 2015 | ||
| Exogenous Wnt3a | Up | Mouse (in vitro ESC differentiation) | Increase in HSPCs | N/A | Tx: d4 | CFC assay | Goessling et al. Cell 2009 | ||
| Exogenous Wnt3a | Up | Mouse (in vitro ESC differentiation) | Increase in HSPCs | N/A | d5-10 | Increase in blood markers by qPCR (CD31, CD45, VE-Cad, Bh1-globin) | Naito et al. PNAS 2006 | ||
| Exogenous Dkk1 | Down | Mouse (in vitro ESC differentiation) | Decrease in primitive blood | N/A | d4 - 6 | Decrease in primitive erythrocyte colonies | Nostro et al. Cell Stem Cell 2008 | ||
| Exogenous DKK1 | Down | Mouse (in vitro ESC differentiation) | Decrease in hematopoietic cells | Ubiquitous | d2-4 | Decrease in Hbb-y expression by qPCR | Rai et al. Stem Cells and Development 2012 | ||
| Cytoplasmic | GSK3B inhibition | Up | Mouse (AGM explants, E10.5) | Increase in HSCs | AGM | E10.5 | SB216763, CFC assay, hematopoietic reconstitution assay | Ruiz-Herguido et al. JEM 2012 | |
| B-catenin inhibition | Down | Mouse (AGM explants, E10.5) | Decrease in HSCs | AGM | E10.5 | PKF-115, CFC assay, hematopoietic reconstitution assay | Ruiz-Herguido et al. JEM 2012 | ||
| Stabilized B-catenin overexpression | Up | Mouse (in vitro ESC differentiation) | Increase in primitive blood | N/A | d4 - 6 | Increase in primitive erythrocyte colonies | Nostro et al. Cell Stem Cell 2008 | ||
| B-catenin | Down | Mouse (in vivo) | Decrease in EMPs | Cdh5:Cre; conditional B-cat | E9.5 - 10.5 | CFC assay, focus on yolk sac | Frame et al. Stem Cells 2016 | ||
| B-catenin | Down | Mouse (in vivo) | Decrease in HSCs | AGM (VECad-Cre) | E10.5-11.5 | CFC assay; mutants had hematopoietic and vascular defects | Ruiz-Herguido et al. JEM 2012 | ||
| B-catenin | Down | Mouse (in vivo) | No effect on HSCs | HSCs (Vav-Cre) | E12.5 onward | Adult analysis; Wnt is required in the endothelium | Ruiz-Herguido et al. JEM 2012 | ||
| B-catenin | Down | Mouse (in vivo) | No effect on HSC number | HSCs (Vav-Cre) | E12.5 onward | Decreased HSC function - poor reconstitution capacity | Zhao et al. Cancer Cell 2007 | ||
| Zebrafish | Extracellular | wnt8 overexpression | Up | Zebrafish (Tg) | Increase in HSCs | Ubiquitous | 10 somite stage | hsp:wnt8 (8a); increase in cmyb+ cells at 36hpf; Wnt regulated by PGE2 | Goessling et al. Cell 2009 |
| wnt9a | Down | Zebrafish (MO and Tg) | Decrease in HSC emergence, specification OK | Somite | pre-20 hpf | Decrease in an aortic expansion of HSCs | Grainger and Richter et al. Cell Reports 2016 | ||
| wnt16 | Down | Zebrafish (MO) | Lack of HSC specification | Somite | pre-15 hpf | Sets up Notch cue needed for specification | Clements et al., Nature 2011 | ||
| dkk1 overexpression | Down | Zebrafish (Tg) | Decrease in HSCs | Ubiquitous | 12 somite stage | hsp:dkk1; decrease in cmyb+ cells at 36 hpf; Wnt regulated by PGE2 | Goessling et al. Cell 2009 | ||
| Porcupine inhibition (no Wnt secretion) | Down | Zebrafish (drug) | Decrease in HSCs | Ubiquitous | 1ss - 40 hpf | IWP-2, decrease in flk1/cmyb+ cells | Grainger and Richter et al. Cell Reports 2016 | ||
| Cytoplasmic | axin1 overexpression | Down | Zebrafish (Tg) | Decrease in HSCs | Ubiquitous | 11 somite stage | hsp:axin1; decrease in cmyb+ cells at 36 hpf; Wnt regulated by PGE2 | Goessling et al. Cell 2009 | |
| increased Axin - Lrp6 interaction | Up | Zebrafish (drug) | Increased HSCs | Ubiquitous | 3ss - 36 hpf | HLY78, decreased cmyb+ cells | Wang et al. Nature Chemical Biology 2013 | ||
| Tankyrase inhibition | Down | Zebrafish (drug) | Decreased HSCs | Ubiquitous | 3ss - 36 hpf | XAV929, decreased cmyb+ cells | Wang et al. Nature Chemical Biology 2013 | ||
| Constitutively active B-catenin | Up | Zebrafish (Tg) | Increased HSCs | Endothelium | 10 - 40 hpf | Increase in cmyb+ cells | Grainger and Richter et al. Cell Reports 2016 | ||
| GSK3B inhibition | Up | Zebrafish (drug) | Increase in HSCs | Ubiquitous | 1ss - 40 hpf | LiCl, increased flk1/cmyb+ cells | Grainger and Richter et al. Cell Reports 2016 | ||
| Nuclear | dntcf overexpression | Down | Zebrafish (Tg) | Lack of primitive blood gata1 expression in PLM | Ubiquitous | 8h | Signals coordinately with BMP to turn on Cdx and Hox genes | Lengerke et al., Cell Stem Cell 2008 | |
| dntcf overexpression | Down | Zebrafish (Tg) | Increase in HSCs | Ubiquitous | 13 somite stage | hsp:dntcf; increase in cmyb+ cells at 36 hpf; Wnt regulated by PGE2 | Goessling et al. Cell 2009 | ||
| dntcf overexpression | Down | Zebrafish (Tg) | Decrease in HSC emergence, specification OK | Hemogenic endothelium (gata2b:Gal4) | pre-20 hpf | Decrease in an aortic expansion of HSCs | Grainger and Richter et al. Cell Reports 2016 | ||