TY - JOUR
T1 - Norrin, Frizzled-4, and Lrp5 Signaling in Endothelial Cells Controls a Genetic Program for Retinal Vascularization
AU - Ye, Xin
AU - Wang, Yanshu
AU - Cahill, Hugh
AU - Yu, Minzhong
AU - Badea, Tudor C.
AU - Smallwood, Philip M.
AU - Peachey, Neal S.
AU - Nathans, Jeremy
N1 - Funding Information:
The authors thank Elke Stein, Shin Kang, and Dwight Bergles for helpful discussions; Chip Hawkins and the JHMI transgenic core for blastocyst injection; Lawrence Chan, Milan Jamrich, Eric Swindell, Ralf Adams, and Masashi Yanagisawa for mouse lines; Se-Jin Lee for the mouse ES cell genomic library; Huimin Yu for the Norrin-expressing 293 cell line; Corrinne Lobe for the Z/AP plasmid; Tom Rotolo for the Z/AP targeting vector; William Guggino for the use of his fluorescent microscope; Hongjun Song for advice on producing the lentivirus; Linda Orzolek, Ira Maine, Haiping Hao, and Connie Talbot for microarray support; Yifeng Zhang and Markus Meister for advice on microelectrode array recording; and David Ginty, Stewart Hendry, Se-Jin Lee, Amir Rattner, and Randy Reed for helpful comments on the manuscript. This work was supported by the National Eye Institute, the Howard Hughes Medical Institute, the Foundation Fighting Blindness, and the Veterans Administration.
PY - 2009/10/16
Y1 - 2009/10/16
N2 - Disorders of vascular structure and function play a central role in a wide variety of CNS diseases. Mutations in the Frizzled-4 (Fz4) receptor, Lrp5 coreceptor, or Norrin ligand cause retinal hypovascularization, but the mechanisms by which Norrin/Fz4/Lrp signaling controls vascular development have not been defined. Using mouse genetic and cell culture models, we show that loss of Fz4 signaling in endothelial cells causes defective vascular growth, which leads to chronic but reversible silencing of retinal neurons. Loss of Fz4 in all endothelial cells disrupts the blood brain barrier in the cerebellum, whereas excessive Fz4 signaling disrupts embryonic angiogenesis. Sox17, a transcription factor that is upregulated by Norrin/Fz4/Lrp signaling, plays a central role in inducing the angiogenic program controlled by Norrin/Fz4/Lrp. These experiments establish a cellular basis for retinal hypovascularization diseases due to insufficient Frizzled signaling, and they suggest a broader role for Frizzled signaling in vascular growth, remodeling, maintenance, and disease.
AB - Disorders of vascular structure and function play a central role in a wide variety of CNS diseases. Mutations in the Frizzled-4 (Fz4) receptor, Lrp5 coreceptor, or Norrin ligand cause retinal hypovascularization, but the mechanisms by which Norrin/Fz4/Lrp signaling controls vascular development have not been defined. Using mouse genetic and cell culture models, we show that loss of Fz4 signaling in endothelial cells causes defective vascular growth, which leads to chronic but reversible silencing of retinal neurons. Loss of Fz4 in all endothelial cells disrupts the blood brain barrier in the cerebellum, whereas excessive Fz4 signaling disrupts embryonic angiogenesis. Sox17, a transcription factor that is upregulated by Norrin/Fz4/Lrp signaling, plays a central role in inducing the angiogenic program controlled by Norrin/Fz4/Lrp. These experiments establish a cellular basis for retinal hypovascularization diseases due to insufficient Frizzled signaling, and they suggest a broader role for Frizzled signaling in vascular growth, remodeling, maintenance, and disease.
KW - DEVBIO
KW - HUMDISEASE
KW - SIGNALING
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U2 - 10.1016/j.cell.2009.07.047
DO - 10.1016/j.cell.2009.07.047
M3 - Article
C2 - 19837032
AN - SCOPUS:70349816655
SN - 0092-8674
VL - 139
SP - 285
EP - 298
JO - Cell
JF - Cell
IS - 2
ER -