WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature


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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Figure 1: Regression of the hyaloid vessels is macrophage-dependent.
Figure 2: The WNT pathway response in VECs is required for hyaloid vessel regression.
Figure 3: WNT7b is required for hyaloid vessel regression and is expressed in macrophages.
Figure 4: Macrophages are a critical paracrine source of WNT7b required for hyaloid vessel regression.


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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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Correspondence to Richard A. Lang.

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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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