Abstract
Macrophages have a critical role in inflammatory and immune responses through their ability to recognize and engulf apoptotic cells1. Here we show that macrophages initiate a cell-death programme in target cells by activating the canonical WNT pathway. We show in mice that macrophage WNT7b is a short-range paracrine signal required for WNT-pathway responses and programmed cell death in the vascular endothelial cells of the temporary hyaloid vessels of the developing eye. These findings indicate that macrophages can use WNT ligands to influence cell-fate decisions—including cell death—in adjacent cells, and raise the possibility that they do so in many different cellular contexts.
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References
Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Rev. Immunol. 2, 965–975 (2002)
Lang, R. A. & Bishop, M. J. Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 74, 453–462 (1993)
Diez-Roux, G. & Lang, R. A. Macrophages induce apoptosis in normal cells in vivo. Development 124, 3633–3638 (1997)
Hoeppner, D. J., Hengartner, M. O. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 (2001)
Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001)
McKercher, S. R. et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 15, 5647–5658 (1996)
Ito, M. & Yoshioka, M. Regression of the hyaloid vessels and pupillary membrane of the mouse. Anat. Embryol. (Berl.) 200, 403–411 (1999)
Nusse, R. WNT targets. Repression and activation. Trends Genet. 15, 1–3 (1999)
Huelsken, J. & Birchmeier, W. New aspects of Wnt signalling pathways in higher vertebrates. Curr. Opin. Genet. Dev. 11, 547–553 (2001)
Ishikawa, T. et al. Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis. Development 128, 25–33 (2001)
Xu, Q. et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand–receptor pair. Cell 116, 883–895 (2004)
Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signalling. Cell 103, 311–320 (2000)
He, X., Semenov, M., Tamai, K. & Zeng, X. LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signalling: arrows point the way. Development 131, 1663–1677 (2004)
Perrimon, N. Serpentine proteins slither into the wingless and hedgehog fields. Cell 86, 513–516 (1996)
Behrens, J. et al. Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382, 638–642 (1996)
Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001)
Kato, M. et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biol. 157, 303–314 (2002)
van Genderen, C. et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. 8, 2691–2703 (1994)
DasGupta, R. & Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557–4568 (1999)
Goodwin, A. M. & D'Amore, P. A. Wnt signalling in the vasculature. Angiogenesis 5, 1–9 (2002)
Shu, W., Jiang, Y. Q., Lu, M. M. & Morrisey, E. E. Wnt7b regulates mesenchymal proliferation and vascular development in the lung. Development 129, 4831–4842 (2002)
Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003)
Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004)
Smith, K. et al. Up-regulation of macrophage Wnt gene expression in adenoma–carcinoma progression of human colorectal cancer. Br. J. Cancer 81, 496–502 (1999)
Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004)
Frade, J. M. & Barde, Y. A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 35–41 (1998)
Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005)
Diez-Roux, G., Argilla, M., Makarenkova, H., Ko, K. & Lang, R. A. Macrophages kill capillary cells in G1 phase of the cell cycle during programmed vascular regression. Development 126, 2141–2147 (1999)
Dann, C. E. et al. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86–90 (2001)
Acknowledgements
We thank: P. Speeg for technical assistance; E. Fuchs, L. Niswander and C. Dean for the TOPGAL mice; S. McKercher and R. Maki for the PU.1-null mice; L. Chan for the Lrp5-null mice; and, R. Grosschedl for the Lef1-null mice. We are indebted to Q. Xu and J. Nathans for providing the SuperTOPFLASH cell line and for the Fzd and Norrin expression plasmids. This work was supported by NIH grants to E.E.M., A.P.M., G.K. and R.A.L. G.K. was also supported by funds from the March of Dimes, and R.A.L. by funds from the Abrahamson Pediatric Eye Institute Endowment at the Children's Hospital Medical Center of Cincinnati.
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Supplementary information
Supplementary Figure S1
Pupillary membrane persistence in the PU.1 mutant mouse. Pupillary membrane is persistent in the PU.1 mutant mouse. (PDF 830 kb)
Supplementary Figure S2
Assessment of Wnt pathway stimulation by, and Wnt gene expression in, hyaloid macrophages. This figure shows that macrophages can stimulate cellular responses in hyaloid VECs that are characteristic of Wnt pathway responses and that macrophages can express Wnt ligand genes. (PDF 746 kb)
Supplementary Figure S3
Generation of the Wnt7bd1allele. This figure shows the gene-targeting scheme for generation of the Wnt7bd1 allele. (PDF 67 kb)
Supplementary Figure S4
Assessment of Fzd receptors in mediating Wnt7b signalling. Supplementary Figure S4 shows that Fzd4 can mediate Wnt7b signalling and that Fzd4 is expressed in the hyaloid capillaries. (PDF 227 kb)
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Lobov, I., Rao, S., Carroll, T. et al. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437, 417–421 (2005). https://doi.org/10.1038/nature03928
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DOI: https://doi.org/10.1038/nature03928
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